Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
  • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
  • A61K35/32—Bones; Osteocytes; Osteoblasts; Tendons; Tenocytes; Teeth; Odontoblasts; Cartilage; Chondrocytes; Synovial membrane
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/14—Macromolecular materials
  • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
  • A61L27/24—Collagen
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
  • A61L27/3604—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the human or animal origin of the biological material, e.g. hair, fascia, fish scales, silk, shellac, pericardium, pleura, renal tissue, amniotic membrane, parenchymal tissue, fetal tissue, muscle tissue, fat tissue, enamel
  • A61L27/3608—Bone, e.g. demineralised bone matrix [DBM], bone powder
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
  • A61L27/3641—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix characterised by the site of application in the body
  • A61L27/3645—Connective tissue
  • A61L27/365—Bones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
  • A61L27/42—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having an inorganic matrix
  • A61L27/425—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having an inorganic matrix of phosphorus containing material, e.g. apatite
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
  • A61L27/54—Biologically active materials, e.g. therapeutic substances
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
  • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
  • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
  • A61L2300/22—Lipids, fatty acids, e.g. prostaglandins, oils, fats, waxes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2430/00—Materials or treatment for tissue regeneration
  • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

• the present invention relates to bone matrix compositions, systems, and methods for local release of pharmaceutical agents, particularly agents that promote bone growth.
• Bone defects such as through fractures or other causes can be treated with autologous bone grafts (i.e., bone taken from another part of a patient's body).
• the graft can act as a scaffold to aid in the bone regeneration process.
• This approach to treating bone defects has several drawbacks including the requirement for additional surgery and the morbidity to the donor site.
• CPCs calcium phosphate cements
• acrylic bone cement polymethylmethacrylate acrylic bone cement polymethylmethacrylate
• Synthetic bone fillers have additionally been investigated as drug delivery systems.
• zoledronate-impregnated CPC blocks implanted in the greater omentum were found to decrease bone turnover and to restore bone architecture in ovariectomized rats. Treating a localized bone defect in this fashion, however, results in potentially unnecessary systemic exposure to a drug.
• simvastatin ⁇ - hydroxy acid in CPC was released over one week and promoted osteogenesis using in vitro assay systems. This relatively quick release of drug over just one week may be of insufficient duration where the promotion of bone growth is required for longer periods of time.
• the present invention provides improved compositions and methods related to bone repair and local delivery into a bone of a therapeutic agent.
• the therapeutic agent may be a bone -repairing drug to repair bone defects and otherwise promote bone growth, an agent that treats bone-related pain, an anti-inflammatory agent to treat an
• inflammation-related condition e.g., arthritis
• an anti-cancer drug to treat bone cancer
• an antimicrobial agent to treat or prevent infection at the treatment site.
• One aspect of the invention provides a bone composition that includes a drug- carrier mixture and a bone matrix or collagen sponge.
• the drug- carrier mixture includes a therapeutic agent and a calcium phosphate cement, and the bone matrix is at least partially demineralized.
• Another aspect of the invention provides a bone repair composition that includes a drug-carrier mixture and a bone matrix or collagen sponge.
• the drug-carrier mixture includes a bone-repairing drug and a calcium phosphate cement, and the bone matrix is at least partially demineralized.
• Another aspect of the invention provides a method of repairing bone or increasing bone density by locally delivering a bone -repairing drug to a bone defect in a patient.
• the bone-repairing drug is delivered from a bone repair composition that includes a drug-carrier mixture and a bone matrix that is at least partially demineralized.
• Another aspect of the invention provides a bone composition that includes a solid insert comprising a therapeutic agent that is embedded in a set non-ceramic calcium phosphate cement, the therapeutic agent being distributed substantially homogeneously throughout the set non-ceramic calcium phosphate cement.
• Still another aspect of the invention provides bone repair composition that includes a solid insert comprising a bone-repairing drug that is embedded in a set non- ceramic calcium phosphate cement, the therapeutic agent being distributed substantially homogeneously throughout the set non-ceramic calcium phosphate cement.
• Yet another aspect of the invention provides a method of repairing bone or increasing bone density by locally delivering a bone -repairing drug to the bone of a patient with a bone repair composition that includes a solid insert comprising a bone- repairing drug that is embedded in a set non-ceramic calcium phosphate cement, the therapeutic agent being distributed substantially homogeneously throughout the set non- ceramic calcium phosphate cement.
• the bone-repairing drug comprises a compound that activates osteoblasts.
• the bone -repairing drug inhibits osteoclasts.
• the bone -repairing drug comprises one or more of PGEl , PGE2, an EP2 agonist, EP4 receptor agonist, an EP2/EP4 dual agonist, an organic bisphosphonate; a cathepsin K inhibitor; an estrogen or an estrogen receptor modulator; calcitonin; an inhibitor of osteoclast proton ATPase; an inhibitor of HMG-CoA reductase; an integrin receptor antagonist; a RANKL inhibitor; a bone anabolic agent; a bone morphogenetic agent; Vitamin D or a synthetic Vitamin D analogue; an androgen or an androgen receptor modulator; a SOST inhibitor; platelet-derived growth factor; and the pharmaceutically acceptable salts and mixtures thereof.
• the bone-repairing drug comprises a compound of formula (I),
• G 1 is O, C(O), S, S(O), S(0) 2 , or NR 8 ; wherein R 8 is H, C C 4 alkyl, or C C 4 alkylcarbonyl;
• R 1 is COOR 10 , CONR 10 R n , CH 2 OR 10 , S0 3 R 10 , SO 2 NR 10 R n , PO(OR 10 ) 2 , or tetrazol-5-yl;
• R 10 is H, Ci-C 4 alkyl, or aryl
• R 11 is H, C 1 -C 4 alkyl, COR 12 , OR 10 , or S0 2 R 12 ;
• R 12 is C 1 -C 4 alkyl
• R 13 at each occurrence, is independently H or Ci-C 4 alkyl
• L 2 is -CH 2 - or a bond
• R 4 and R 5 are each independently H, F, CF 3 , or C C 4 alkyl; or R 4 and R 5 together with the carbon to which they are attached form a C 3 -C 5 cycloalkyl, ,
• R 6 is aryl, heteroaryl, C 3 -C 10 alkyl, C 3 -C 10 alkenyl, C 3 -C 10 alkynyl, C 3 - C 10 haloalkyl, C 3 -C 10 haloalkenyl, C 3 -C 10 haloalkynyl, or L 3 -R 7 ; wherein the aryl and heteroaryl are optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C 1 -C 4 alkyl, C C 3 haloalkyl, cyano, halogen, C C 3 alkoxy, C C 3 haloalkoxy; and -C 1 -C 3 alkylene-C 1 -C 3 alkoxy; and wherein the C 3 -C 10 alkyl, C 3 -C 10 alkenyl, C 3 - C 10 alkynyl, C 3 -C 10 haloalkyl, C 3 -C 10
• R 10' is H, C 1 -C 4 alkyl, or aryl
• R 11' is H, C 1 -C 4 alkyl, COR 12' , OR 10' , or S0 2 R 12' ;
• R 12 is C1-C4 alkyl;
• G 3 is O, C(O), S, S(O), S(0) 2 , or NR 9 ; wherein R 9 is H, C C 4 alkyl, or C C 4 alkylcarbonyl;
• w eren s optona y su sttute wt , , or su sttuents seecte rom t e group consisting of C C 4 alkyl, C C 3 haloalkyl, cyano, halogen, C C 3 alkoxy, and C C 3 haloalkoxy;
• G 5 is ,oA O , wherein G 5 is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of C C 4 alkyl, C C 3 haloalkyl, cyano, halogen, Q-Qalkoxy, and C C 3 haloalkoxy;
• R 7 is C 3 -C 8 cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein R 7 is optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of Ci-C 4 alkyl, Ci-C 3 haloalkyl, cyano, halogen, Ci-C 3 alkoxy, Ci-C 3 haloalkoxy, and -C C 3 alky lene-C ! -C 3 alkoxy ;
• the bone-repairing drug comprises a compound of formula (la)
• the bone -repairing drug comprises a compound of formula (II)
• FIG. 1 depicts data showing the effect of Compound 2C on stimulation of bone growth in the rat calvarial defect model.
• FIG. 2 depicts data showing the effect of Compound 2E' on stimulation of bone growth in the rat calvarial defect model using a demineralized bone matrix putty.
• FIG. 3 illustrates the effect of varying proportions of a-tricalcium phosphate cement and ⁇ -tricalcium phosphate cement on cement dissolution rate in a physiological medium.
• FIG. 4 depicts the effect of Compound 2E' on stimulation of bone growth in the rat calvarial defect model using intact demineralized bone matrix.
• FIG. 5 depicts the effect of Compound 2E' on bone mineral density in a rat femur following an osteotomy.
• FIG. 6 depicts the effect of Compound 28C on femoral bone density in a rat following an osteotomy.
• the bone compositions of the invention include a drug-carrier mixture and a bone matrix that is at least partially demineralized or a collagen sponge.
• the bone matrix component/collagen sponge is omitted from the bone composition.
• the drug-carrier mixture is in the form of a solid insert of a set non-ceramic calcium phosphate cement with a drug embedded substantially homogeneously throughout the cement.
• Drugs included in the drug-carrier mixture include agents that are capable of stimulating, promoting, enhancing, or inducing bone formation, or inhibiting bone resorption. Bone -repairing drugs or other agents may alleviate pain and/or inflammation at the treatment site, or treat cancer or treat or prevent a microbial infection.
• the drug-carrier mixture provides for the release of drug at a treatment site.
• the drug-carrier mixture sustains release of the drug for prolonged periods of time.
• the drug-carrier mixture is prepared by mixing a drug with a suitable carrier material such as, for example, a calcium phosphate cement powder. Depending on the particular embodiment, the mixture may be further processed by setting and grinding it into a ground powder.
• the drug-carrier mixture may be combined with a suitable bone matrix material, as described below, to form a bone composition of the invention.
• the bone-repair compositions may include a collagen sponge. The bone composition may then be applied to a treatment site, such as, for example, by implantation or injection at the site of a bone defect.
• CPCs Calcium Phosphate cements
• a-TCP tri-calcium phosphate
• ⁇ -TCP ⁇ - tri-calcium phosphate
• Other CPCs that may be used include combinations of dicalcium phosphate and tetracalcium phosphate.
• Commercially available calcium phosphate cement may also be used such as Hydroset (sold by Stryker Corp), which was used in the Examples disclosed herein. Hydroset is a soft tri-calcium phosphate cement that has the characteristics of a mixture of a-TCP and ⁇ -TCP (1 :3).
• the calcium phosphate cements and mixtures thereof may also be seeded with hydroxyapatite (e.g., 2.5 % wt./wt. hydroxyapatite crystals).
• a-TCP and ⁇ -TCP may be used in various ratios.
• the CPC comprises a mixture of a-TCP and ⁇ -TCP (1 :3) and optionally a seed of hydroxyapatite.
• a-TCP and ⁇ -TCP may be used in ratios of 1 : 1 or 1 :0. In other
• the CPC is a-TCP cement seeded with 2.5% hydroxyapatite, which produces a harder cement upon setting.
• the bone compositions of the invention may include a bone matrix that is at least partially demineralized.
• the bone matrix may be a demineralized bone matrix putty, or an intact bone matrix that is either partially or wholly demineralized.
• An intact bone matrix may be used in a bone graft procedure and act as a scaffold for delivery of a bone- repairing drug.
• a bone matrix may facilitate repair of a bone defect by attracting osteoblasts and stimulating their differentiation to promote bone formation and mineralization.
• a bone matrix may have osteooconductive, osteoinductive and osteogenic capabilities.
• Human demineralized bone matrix putty can be obtained from commercial sources such as Puros Demineralized Bone Matrix Putty manufactured by RTI Biologies (Alachua, FL). Demineralized bone matrix putty can also be made by the method described by Urist & Dowell (Inductive Substratum for Osteogenesis in Pellets of Particulate Bone Matrix, Clin. Orthop. Relat. Res. , 1968, 61, 61-78.). The method involves bone demineralization and defatting and cutting the solid demineralized bone into small pieces that are ground into a course powder under liquid nitrogen. Upon thawing, the ground demineralized bone matrix takes on the consistency of a putty.
• Intact demineralized bone matrix can be made by the method described by Urist & Dowell (1968). After removal from the donor animal the bone is cleaned of attached tissue and placed in a 0.3 N HCL solution overnight at 4 °C. The following day the bone is imaged on a cone beam X-ray CT scanner (Vatech Pax3-Duo) and the extent of mineralization is assessed. If any remaining mineralization is observed the bone is placed in a fresh acid solution and incubated overnight at 4 °C. This process is repeated until no remaining mineral is observed.
• the demineralized bone is then defatted by incubating in a 100% ethanol solution for 4 h on a rotator at room temperature. Following defatting, the demineralized bone is stored at 4 °C in phosphate buffered saline until use.
• the demineralization and defatting procedure creates dosing spaces into which a drug-CPC mixture may be loaded.
• a typical dosing space is a hole drilled into the matrix either before or after demineralization of the bone.
• the bone material may alternatively be partially demineralized.
• Drug-CPC mixtures can be prepared by dissolving a drug in an appropriate solvent such as, for example, ethanol and adding the solution to a calcium phosphate cement powder. After the solvent has been vented off, the cement powder is mixed to distribute the drug evenly (i.e., homogeneously) throughout the powder and is then wetted with the setting solution appropriate for each cement. The cement-drug mix is mixed thoroughly for about 1 minute as the cement begins to set. The mixing and setting process results in the drug being embedded substantially homogeneously throughout the set CPC, rather than simply adsorbed onto the surface.
• an appropriate solvent such as, for example, ethanol
• the cement is allowed to set overnight at room temperature before being ground to a fine powder in a mortar and pestle.
• Amounts of drug that may be loaded into CPC range from about 3 ng drug per gram of CPC to about 3 mg of drug per gram of CPC.
• the CPC serves to encapsulate the drug so that it is released slowly over time to sustain the therapeutic effects of the drug.
• the setting procedure may convert the CPC into hydroxyapatite by a dissolution-precipitation process.
• a-tricalcium phosphate can convert to hydroxyapatite during the setting procedure. This conversion may be assisted by the addition of seed crystals of hydroxyapatite.
• ⁇ -tricalcium phosphate does not convert to hydroxyapatite.
• the dissolution- precipitation process may produce a crystalline CPC or a crystalline hydroxyapatite.
• the setting process produces a set non-ceramic calcium phosphate cement.
• the cement may be in whole, or in part, a set non-ceramic
• the set CPC may be resorbed after implantation at the treatment site (e.g., a bone defect or area of low bone density) and replaced by bone.
• the drug-CPC mixture may be used either as a solid insert or ground to a powder, depending on the particular application.
• the solid insert of drug-CPC may be shaped as desired for implantation.
• the solid insert of drug-CPC may be cut or abraded by any suitable technique, such as, for example, trimming with a scalpel, grinding, filing, etc.
• a solid insert of drug-CPC may be implanted directly into a trephined bone or into an intact demineralized bone matrix as described below.
• a bone composition comprises a mixture of a drug-CPC mixture with DBM putty.
• the ratio of drug-CPC mixture:DBM putty may be from about 1 :20 wt(mg)/vol ⁇ L) to about 1 :4 wt(mg)/vol ⁇ L) and any ratios in between. In some embodiments, the ratio may range from 1 : 19 wt(mg)/vol ⁇ L) to about 1 :6.7 wt(mg)/vol ⁇ L). In one embodiment, the ratio of drug-CPC mixture:DBM putty is about 1 :8 wt(mg)/vol ⁇ L).
• composition can be made, for example, by adding a fine powder of a drug-CPC mixture to (DBM) putty in amounts of 1 mg of drug-CPC mix to 8 ⁇ , of putty, followed by thorough mixing.
• the drug-CPC-DBM mixture is then stored at 4 °C until use.
• the drug-CPC-DBM putty is applied to a bone defect (e.g., by injection) in sufficient quantity so as to fill the bone defect.
• the defect is filled entirely.
• a method of repairing bone or increasing bone density includes locally delivering a bone-repairing drug to a bone of a patient where the drug is locally delivered by a mixture of drug-CPC-DBM putty or drug-CPC-collagen sponge, either of which may be implanted into the bone in need of repair or increased density.
• a pain-relieving drug, an anti- inflammatory agent, an antimicrobial agent, or an anti-cancer agent is locally delivered from the mixture of drug- CPC-DBM putty or drug-CPC-collagen sponge.
• the CPC used in the composition is made from a mixture of a-TCP and ⁇ -TCP (1 :3), with optional hydroxyapatite, and the drug-CPC mixture:DBM putty ratio is about 1 :8 wt(mg)/vol ⁇ L). In other embodiments, the ratio of a-TCP to ⁇ -TCP is 1 : 1 or 1 :0.
• the drug in the foregoing composition is a bone-repairing drug, as defined and described herein. In some embodiments, for example, the bone-repairing drug is an EP4 agonist.
• a bone composition comprises a mixture of a drug-CPC mixture with a collagen sponge.
• a bone composition according to this embodiment may be prepared by dampening a collagen sponge with a physiological salt solution and applying a drug-CPC mixture to adhere the cement powder to the outside of the sponge. The loaded sponge may then be inserted into the bone defect.
• the CPC used in the composition is made from a mixture of a-TCP and ⁇ -TCP (1 :3), with optional hydroxyapatite.
• the ratio of a-TCP to ⁇ -TCP is 1 : 1 or 1 :0.
• the drug in the foregoing composition is a bone -repairing drug, as defined and described herein.
• the bone-repairing drug is an EP4 agonist.
• a bone composition comprises a mixture of a drug-CPC mixture with intact DBM (IDBM).
• the drug-CPC-IDBM is created by loading a drug-CPC mixture into the dosing spaces of intact solid
• demineralized bone matrix In practice, fresh drug-CPC powder is prepared and then set with the appropriate setting solution. During the setting phase the drug-cement mixture is placed into the dosing space created in the intact demineralized bone matrix. The cement is allowed to set in situ at 4 °C overnight in a water -saturated atmosphere after which the drug-CPC-IDBM is stored in a water -saturated atmosphere at 4 °C until use.
• the drug-CPC mixture may be prepared as a solid insert that may be loaded into a dosing space created in the IDBM.
• the CPC used in the drug-CPC-IDBM is made from a mixture of a-TCP and ⁇ -TCP (1 :3), with optional hydroxyapatite.
• the ratio of a-TCP to ⁇ -TCP is 1 : 1 or 1 :0.
• the drug in the foregoing composition is a bone -repairing drug, as defined and described herein.
• the bone-repairing drug is an EP4 agonist.
• the intact DBM is suitable for use in repairing a large bone defect.
• the drug-CPC-IDBM may be used in the replacement of a piece of missing bone that is both highly shaped and all of the original bone is lost, e.g. craniofacial injury or long bone injury over 3 cm.
• a piece of donor bone which matches the defect would be demineralized as described herein, loaded with the drug-CPC mixture and the mixture set.
• the drug-CPC-IDBM may then be surgically implanted at the site of the missing bone.
• the drug-CPC-IDBM may be used to replace missing bone in which some of the original bone structure is still present, e.g. alveolar ridge augmentation.
• a block of drug-CPC-IDBM would be trimmed to the desired shape by the surgeon before placement at the bone defect site.
• the drug-CPC-IDBM may be used in procedures that are more routine, e.g. vertebral fusion where the surgeon would be supplied with a pre-shaped piece of drug-CPC-IDBM which would be placed in the surgical site.
• the drug-CPC-IDBM can be used to fill large defects in which the surgeon has poor access or the surgeon would prefer a filling material that is moldable, e.g. sinus lift.
• the superior osteoconductive activity of the solid DBM is still maintained but because the DBM is now shredded into smaller pieces it has the filling activity more like that of a putty.
• Shredded drug-CPC- IDBM may be combined with DBM putty to make a moldable void filler like putty but with much of the superior osteoconductive activity associated with the intact DBM.
• the drug-CPC-IDBM may be formed (e.g. cut) into chips.
• the drug-CPC-IDBM may be formed into strips.
• a method of repairing bone or increasing bone density includes locally delivering a bone-repairing drug to a bone of a patient where the drug is locally delivered by a composition of drug-CPC-IDBM, which may be implanted into the bone in need of repair or increased density.
• a pain- relieving drug, an anti- inflammatory agent, an antimicrobial agent, or an anti-cancer agent is locally delivered from the mixture of drug-CPC-IDBM.
• a bone composition comprises a mixture of a drug-CPC mixture with intact partially demineralized bone matrix (PDBM).
• the drug-CPC-PDBM is created in the same fashion as described above for IDBM except that partially demineralized bone matrix is used instead.
• the CPC used in the drug-CPC-PDBM is made from a mixture of a-TCP and ⁇ -TCP (1 :3), with optional hydroxy apatite.
• the ratio of a-TCP to ⁇ -TCP is 1 : 1 or 1 :0.
• the drug in the foregoing composition is a bone-repairing drug, as defined and described herein.
• the bone- repairing drug is an EP4 agonist.
• the drug-CPC-PDBM may generally be used in the same fashion as that described above for the drug-CPC-IDBM.
• the drug-CPC-PDBM may be preferred in the treatment of a very large bone defect where the mechanical strength of the newly placed insert is important for maintaining space and shape (e.g. loss of long bone greater than 3 cm).
• An implant made from PDBM has greater mechanical strength since only the outer layers of bone are demineralized and the inner part remains mineralized.
• the demineralized bone offers a substrate for osseointegration with the host and the mineralized bone provides rigidity to the insert for mechanical support while integration occurs.
• a method of repairing bone or increasing bone density includes locally delivering a bone-repairing drug to a bone of a patient where the drug is locally delivered by a composition of drug-CPC-PDBM, which may be implanted into the bone in need of repair or increased density.
• a pain- relieving drug, an anti- inflammatory agent, an antimicrobial agent, or an anti-cancer agent is locally delivered from the mixture of drug-CPC-PDBM.
• a drug-CPC mixture may be cast as a solid insert for direct insertion into bone.
• the solid insert may be adapted for insertion into a trephined bone by forming the solid insert into a shape that is complementary to the insertion site.
• the shaping of the solid insert includes, for example, the cutting and abrading methods discussed above.
• the CPC used as a solid insert is made from a mixture of a-TCP and ⁇ -TCP (1 :3), with optional hydroxy apatite.
• the ratio of a-TCP to ⁇ -TCP is 1 : 1 or 1 :0.
• the drug in the foregoing composition is a bone-repairing drug, as defined and described herein.
• the bone-repairing drug may be an EP4 agonist.
• the drug is embedded substantially homogeneously throughout the set calcium phosphate cement as a consequence of the mixing and setting procedure.
• the mixing and setting process produces a calcium phosphate cement that is non-ceramic.
• the set non-ceramic calcium phosphate cement is a crystalline calcium phosphate.
• the set non-ceramic calcium phosphate cement contains some amount of crystalline hydroxyapatite, depending on the type(s) of calcium phosphate cement used in the setting procedure.
• a method of repairing bone or increasing bone density in a patient includes locally delivering a bone-repairing drug to a bone in the patient where the bone repairing drug is delivered from a solid insert comprising a therapeutically effective amount of the bone -repairing drug embedded substantially homogeneously throughout the set non-ceramic calcium phosphate cement.
• the bone is a trephined bone and the bone repair composition (solid insert) is implanted into the trephined bone.
• one or more of a pain-relieving drug, an antiinflammatory agent, an antimicrobial agent, or an anti-cancer agent is locally delivered from the solid insert bone repair composition.
• compositions of the invention provide a vehicle for release of drugs at a treatment site following a procedure to repair a bone defect.
• the release is a sustained release.
• the sustained release of a drug at the treatment site prolongs the therapeutic drug effect in order to promote healing at the treatment site.
• drug release from the drug-CPC mixture may be controlled by one or both of: (1) dissolution of the cement in the surrounding physiological medium; and (2) degradation of the cement by osteoclasts, ⁇ - TCP has greater solubility in physiological solutions than a-TCP and so greater proportions of ⁇ -TCP in the drug-CPC mixture may result in a greater degree of drug release by a dissolution mechanism. It has been found that increasing the proportion of a- TCP in a CPC mixture of a-TCP and ⁇ -TCP decreases the extent of CPC dissolution after 2 days at 37 °C in phosphate buffered saline (FIG. 3).
• a more soluble cement may result in greater amounts of drug being released by a dissolution process.
• a harder and less soluble cement e.g., a-TCP
• a-TCP a harder and less soluble cement
• the rate of drug release may be varied by adjusting the proportions of the particular cements used in the drug-CPC mixture.
• the release of drug by dissolution is a passive process that is primarily dependent on the solubility of the cement and not on the structure of the drug.
• dissolution-mediated release is expected to take place independent of the structure or functionalities present in a particular drug.
• the rate of release of most drugs by dissolution is expected to be approximately the same, with the release rate being governed by the choice of cement.
• drugs that inhibit osteoclast activity e.g., bisphosphonates, estrogen receptor modulators
• the inclusion of an osteoclast-inhibiting drug in the drug-CPC mixture provides for more sustained release of drug, particularly where the CPC has higher percentages of a harder, less soluble CPC (e.g., a-TCP).
• drug release rates may be controlled by adjusting the surface area to volume ratio, by manipulating the proportions of soluble and insoluble cements, and by the inclusion of osteoclast-inhibiting drugs in the drug- CPC mixture.
• decreasing the rate of drug release by any of the foregoing mechanisms is preferred for treatments requiring longer term therapy such as in the treatment of bone cancer or osteroporosis.
• a drug be stable to pH 4-5 where a greater proportion is released by the osteoclast-mediated degradation mechanism.
• Drugs with greater sensitivity to the osteoclast environment are preferably embedded in CPCs having a higher proportion of soluble CPC such as ⁇ -TCP. This allows the drug to be released by the passive dissolution process and thereby avoid significant degradation at pH 4-5.
• Release of drug from drug-CPC-IDBM/PDBM operates according to the same principles as release from CPC-DBM putty.
• the CPC set inside the IDBM/PDBM is a solid block, the surface area/volume ratio is much smaller than the ground cement in DBM putty and the rate of CPC turnover is lower in IDBM than in DBM putty.
• the CPC is removed/resorbed and replaced by newly formed bone.
• the drug released in the removal/resorption of the CPC may enhance the rate of new bone formation by modulating osteoblast and osteoclast activity.
• a drug that increases osteoblast numbers may result in the increased osteoblast population continuing to repair/fill a defect for weeks after the drug has dissipated from the site.
• the DBM has no three- dimensional structure and so serves as the raw material for making new bone soft tissue.
• IDBM/PDBM possess much of the three-dimensional structure of the original tissue by virtue of being prepared from whole bone. As such the IDBM/PDBM may serve as a scaffold for the formation of new bone. IDBM/PDBM may thus be remineralized by the host prior to significant resorpti on/replacement of the DBM.
• Drugs released by the bone compositions may promote bone formation by increasing osteoblast activity.
• Certain classes of drugs are known to increase osteoblast activity such as, for example, PGE2, parathyroid hormone, strontium ranelate, EP4 agonists, and activators of Wnt/ -catenin signaling (e.g. a GSK-3 inhibitor, a sclerostin antagonist, a SOST inhibitor).
• osteoclast activity such as, for example, estrogen, estrogen-receptor modulators, organic bis-phosphonates, RANKL inhibitors, cathepsin K inhibitors, inhibitors of osteoclast proton ATPase (e.g., SB242784); inhibitors of HMG-CoA reductase (i.e. a statin), and av 3integrin receptor antagonists.
• Bone-repairing drugs in addition to beneficial effects on bone formation, may incidentally reduce pain at the treatment site as a consequence of effects on bone remodeling. Thus, by increasing bone strength, a bone repair drug may also alleviate bone pain.
• Antiresorptive therapies e.g., bisphosphonates
• a bone -repairing drug may also be loaded in the CPC with one or more pain relieving agents, anti- inflammatory agents, antimicrobial agents, or anti-cancer agents.
• the pain relieving agents may be released from the CPC in the same manner as a bone- repairing drug to provide local relief of bone pain.
• anti-inflammatory drugs may be released from the CPC to reduce local inflammation.
• Antimicrobial agents e.g., antibacterials, antifungals
• Anti-cancer agents may be released from the compositions to treat bone cancer.
• the bone compositions comprise compounds described herein,
• the bone compositions comprising the compound, salt, or solvate described herein may be formulated together with one or more non-toxic pharmaceutically acceptable carriers, either alone or in combination with one or more other medicaments as described hereinabove.
• compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
• microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid and the like.
• the compounds can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids.
• pharmaceutically acceptable salt means those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.
• salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in (J. Pharmaceutical Sciences, 1977, 66: 1 et seq).
• the salts can be prepared in situ during the final isolation and purification of the compounds or separately by reacting a free base function with a suitable organic acid.
• Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethansulfonate (isothionate), lactate, malate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate, 3- phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and
• the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as, but not limited to, methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as, but not limited to, decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
• lower alkyl halides such as, but not limited to, methyl, ethyl, propyl, and butyl chlorides, bromides and iodides
• dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl
• acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid and such organic acids as acetic acid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinic acid and citric acid.
• Basic addition salts can be prepared in situ during the final isolation and purification of compounds by reacting a carboxylic acid-containing moiety with a suitable base such as, but not limited to, the hydroxide, carbonate or bicarbonate of a
• Pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine include, but are not limited to, cations based on alkali metals or alkaline earth metals such as, but not limited to, lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium,
• trimethylamine triethylamine, diethylamine, ethylamine and the like.
• Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
• the bone compositions are useful in treating low bone density due to osteoporosis (Cameron, K. O. et al, Bioorganic and Medicinal Chemistry Letters, 2006, 16, 1799-1802) or glucocorticoid treatment, bone fracture, and bone loss due to periodontal disease, surgical procedures, cancer, or trauma. Further uses of the compositions of the invention include use in increasing bone density in preparation of bone for receiving dental or orthopedic implants, coating of implants for enhanced osseointegration, and use in all forms of spinal fusion.
• the present invention provides methods of treatment comprising administering to a patient in need thereof a bone composition containing a therapeutically effective amount of a bone -repairing drug, as described herein.
• the methods of treatment generally include stimulating, promoting, enhancing, or inducing bone formation, or inhibiting bone resorption.
• the methods of treatment also include, for example, promoting bone remodeling, activating osteoblasts, promoting osteoblast differentiation, inhibiting osteoclasts, increasing the number and activity of osteoblasts, enhancing mean wall thickness, enhancing trabecular bone volume, improving bone architecture, improving trabecular connectivity, increasing cortical thickness, inhibiting bone loss, maintaining/improving bone strength, increasing total bone volume, or volume of the osteoid.
• the methods of treatment also include treating one or more of osteoporosis, bone fracture, low bone density, or periodontal disease.
• one or more bone-repairing drugs is administered by release from a CPC-DBM mixture as described herein.
• a bone-repairing drug is administered from a CPC-DBM mixture in combination with another therapeutic agent administered systemically (e.g., orally).
• a bone -repairing drug may be administered with a bone composition in combination with one or more additional therapeutic agents to treat bone loss or osteoporosis administered systemically.
• the methods of treatment further comprise administration of bone
• compositions to humans, other mammals, and birds locally to the desired site of action for example, into a bone void such as a tooth socket defect, adjacent to an alveolar bone, or a bone defect caused by surgery, trauma, or disease.
• the invention also provides methods of treating bone -related pain
• inflammation, infection and/or bone cancer comprising administering a bone composition containing a therapeutically effective amount of an analgesic, anti-inflammatory agent, an anti-cancer agent, and/or an antimicrobial agent.
• analgesic, anti-inflammatory agent, an anti-cancer agent, and/or an antimicrobial agent comprising administering a bone composition containing a therapeutically effective amount of an analgesic, anti-inflammatory agent, an anti-cancer agent, and/or an antimicrobial agent.
• the methods of treating pain, inflammation, cancer, and/or infection may be combined with any of the foregoing methods of treating bone disorders.
• the phrase "therapeutically effective amount” means sufficient amounts of the compounds to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It is understood, however, that the total dosage of the compounds in the compositions can be decided by the attending physician within the scope of sound medical judgment.
• the specific therapeutically effective dose level for any particular patient can depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the rate of drug release from the composition, the age, body weight, general health and prior medical history, sex and diet of the patient; the delivery method; drugs used in combination or coincidental with the specific compound employed; and like factors well-known in the medical arts.
• Actual dosage levels of active ingredients in the pharmaceutical compositions can be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient and a particular mode of administration.
• Combination therapy includes administration of a single pharmaceutical dosage formulation containing one or more of the compounds described herein and one or more additional pharmaceutical agents, as well as administration of the compounds and each additional pharmaceutical agent, in its own separate pharmaceutical dosage formulation.
• a compound described herein and one or more additional pharmaceutical agents can be administered to the patient together, in a bone composition having a fixed ratio of each active ingredient, or each agent can be administered in separate dosage formulations.
• a patient may be treated by a bone composition delivering an active drug locally at the site of a bone defect in combination with another drug administered systemically.
• the present compounds and one or more additional pharmaceutical agents can be administered at essentially the same time (e.g., concurrently) or at separately staggered times (e.g., sequentially).
• drugs delivered by the compositions of the invention, or a pharmaceutically acceptable salts thereof, or a solvates of either are administered as the active pharmaceutical agent.
• drugs delivered by compositions of the invention or a pharmaceutically acceptable salt thereof, or a solvate of either are administered to a subject and the administered compounds are converted to the active pharmaceutical agent in the subject by chemical or biotransformation.
• bone matrix refers to a demineralized bone matrix putty, intact demineralized bone, or intact partially demineralized bone.
• bone-repairing drug refers to an agent that is capable of stimulating, promoting, enhancing, or inducing bone formation, or inhibiting bone resorption.
• a bone-repairing drug may be an anabolic drug or an anticatabolic drug.
• a bone repairing drug may do one or more of the following: promote bone remodeling, activate osteoblasts, promote osteoblast differentiation, inhibit osteoclasts, increase the number and activity of osteoblasts, enhance mean wall thickness, enhance trabecular bone volume, improve bone architecture, improve trabecular connectivity, increase cortical thickness, inhibit bone loss, maintain/improve bone strength, increase total bone volume, or volume of the osteoid.
• a bone -repairing drug includes, but is not limited to, prostaglandin E2; an EP2 agonist; an EP4 agonist; an EP2/EP4 dual agonist; an organic bisphosphonate (e.g., alendronic acid or sodium alendronate); a cathepsin K inhibitor; an estrogen or an estrogen receptor modulator; calcitonin; an inhibitor of osteoclast proton ATPase; an inhibitor of HMG-CoA reductase (i.e., a statin); an avP3integrin receptor antagonist; a RANKL inhibitor such as denosumab; a bone anabolic agent, such as parathyroid hormone; a bone morphogenic protein (e.g., BMP-2, BMP-4, BMP-7);
• an organic bisphosphonate e.g., alendronic acid or sodium alendronate
• a cathepsin K inhibitor e.g., alendronic acid or sodium alendronate
• Vitamin D or a synthetic Vitamin D analogue such as ED-70; an androgen or an androgen receptor modulator; an activator of Wnt/ -catenin signaling (e.g. a GSK-3 inhibitor, a sclerostin antagonist, a SOST inhibitor); bortezomib; strontium ranelate; platelet-derived growth factor; and the pharmaceutically acceptable salts and mixtures thereof.
• Bone- repairing drugs preferably are not degraded to an inactive form when exposed to a pH of between about 4-5.
• calcium phosphate cement or "calcium phosphate cement composition” as used herein refers to a composition that includes a di-calcium phosphate, a tri-calcium phosphate (e.g., a-tri-calcium phosphate and ⁇ - tri-calcium phosphate) or a tetra-calcium phosphate, or refers to a composition that is made from any of the foregoing, or mixtures thereof by setting.
• a calcium phosphate cement or calcium phosphate cement composition may also include hydroxyapatite incorporated in with a calcium phosphate compound.
• drug-carrier mixture refers to a mixture of a drug incorporated into a calcium phosphate cement composition.
• agonist refers to a compound, the biological effect of which is to mimic the action of the natural agonist PGE2.
• An agonist may have full efficacy (i.e., equivalent to PGE2), partial efficacy (lower maximal efficacy compared to PGE2), or super maximal efficacy (higher maximal efficacy compared to PGE2).
• An agonist with partial efficacy is referred to as a "partial agonist.”
• An agonist with super maximal efficacy is referred to as a "super agonist.”
• alkyl as used herein, means a straight or branched chain saturated hydrocarbon.
• Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n- octyl, n-nonyl, and n-decyl.
• alkenyl as used herein, means a straight or branched chain hydrocarbon and containing at least one carbon-carbon double bond.
• Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2- propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl- l-heptenyl, and 3- decenyl.
• alkynyl means a straight or branched chain hydrocarbon and containing at least one carbon-carbon triple bond. Representative examples include propynyl, butynyl, pentynyl, and the like.
• alkylene means a divalent group derived from a straight or branched chain hydrocarbon.
• Representative examples of alkylene include, but are not limited to, -CH 2 - -CH 2 CH 2 - -CH 2 CH 2 CH 2 - -CH 2 CH(CH 3 )CH 2 - and - CH 2 CH(CH 3 )CH(CH 3 )CH 2 -.
• alkenylene means a divalent group derived from a straight or branched chain hydrocarbon and containing at least one carbon-carbon double bond.
• alkynylene means a divalent group derived from a straight or branched chain hydrocarbon and containing at least one carbon-carbon triple bond.
• Representative examples of alkynylene include, but are not limited to -CH 2 -C ⁇ C- , -CH 2 CH 2 -C ⁇ C- and -C ⁇ C-CH 2 CH(CH 3 )CH 2 -.
• alkoxy means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
• Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, and hexyloxy.
• alkylcarbonyl as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through a C(O) group.
• haloalkyl means, respectively an alkyl, alkenyl, or alkynyl group, as defined herein, in which one, two, three, four, five, six, or seven hydrogen atoms are replaced by halogen.
• representative examples of haloalkyl include, but are not limited to, 2-fluoroethyl, 2,2- difluoroethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trifluoro- l , l-dimethylethyl, and the like.
• haloalkoxy means an alkoxy group, as defined herein, in which one, two, three, four, five, or six hydrogen atoms are replaced by halogen.
• Representative examples of haloalkoxy include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, 2,2-difluoroethoxy, 2- fluoroethoxy, and pentafluoroethoxy.
• aryl means phenyl or a bicyclic aryl.
• the bicyclic aryl is naphthyl, dihydronaphthalenyl, tetrahydronaphthalenyl, indanyl, or indenyl.
• the phenyl and bicyclic aryls are attached to the parent molecular moiety through any carbon atom contained within the phenyl or bicyclic aryl.
• heteroaryl means a monocyclic heteroaryl or a fused bicyclic heteroaryl.
• the monocyclic heteroaryl is a 5 or 6 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S.
• the 5-membered ring contains two double bonds, and one, two, three, or four heteroatoms as ring atoms.
• the 6-membered ring contains three double bonds, and one, two, three or four heteroatoms as ring atoms.
• monocyclic heteroaryl include, but are not limited to, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl.
• the bicyclic heteroaryl is an 8- to 12-membered ring system having a monocyclic heteroaryl fused to an additional ring; wherein the additional ring may be aromatic or partially saturated, and may contain additional heteroatoms.
• Representative examples of bicyclic heteroaryl include, but are not limited to, benzofuranyl, benzoxadiazolyl, 1 ,3-benzothiazolyl, benzimidazolyl, benzodioxolyl, benzothienyl, chromenyl, furopyridinyl, indolyl, indazolyl, isoquinolinyl, naphthyridinyl, oxazolopyridine, quinolinyl, thienopyridinyl, 5,6,7, 8-tetrahydroquinolinyl, 6,7-dihydro-5H-cyclopenta[b]pyridinyl, and 2,3- dihydrofuro[3,2-b]pyridinyl.
• cycloalkyl as used herein, means a carbocyclic ring system containing 3, 4, 5, 6, 7, or 8 carbon atoms and zero heteroatoms as ring atoms, and zero double bonds.
• cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
• the cycloalkyl groups of the present invention may contain an alkylene bridge of 1 , 2, 3, or 4 carbon atoms, linking two non adjacent carbon atoms of the group.
• bridged systems include, but are not limited to, bicyclo[2.2.1 ]heptanyl and bicyclo[2.2.2]octanyl.
• the cycloalkyl groups described herein can be appended to the parent molecular moiety through any substitutable carbon atom.
• heterocycle refers to a monocyclic heterocycle, a bicyclic heterocycle, or a spirocyclic heterocycle.
• the monocyclic heterocycle is a 3, 4, 5, 6, 7, or 8-membered ring containing at least one heteroatom selected from O, N, or S.
• the 3 or 4 membered ring contains one heteroatom and optionally one double bond.
• the 5 -membered ring contains zero or one double bond and one, two or three heteroatoms.
• the 6, 7, or 8-membered ring contains zero, one, or two double bonds, and one, two, or three heteroatoms.
• monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1 ,3-dioxanyl, 1 ,4-dioxanyl, 1 ,3-dioxolanyl , 4,5-dihydroisoxazol-5-yl, 3,4- dihydropyranyl, 1 ,3-dithiolanyl, 1 ,3-dithianyl, imidazolinyl, imidazolidinyl,
• the bicyclic heterocycle is a 5-12-membered ring system having a monocyclic heterocycle fused to a phenyl, a saturated or partially saturated carbocyclic ring, or another monocyclic heterocyclic ring.
• bicyclic heterocycle include, but are not limited to, l,3-benzodioxol-4-yl, 1,3-benzodithiolyl, 3-azabicyclo[3.1.0]hexanyl, hexahydro- 1 H-furo[3,4-c]pyrrolyl, 2,3-dihydro- 1 ,4-benzodioxinyl, 2,3-dihydro- 1 - benzofuranyl, 2,3-dihydro- 1-benzothienyl, 2,3-dihydro- lH-indolyl, and 1,2,3,4- tetrahydroquinolinyl.
• Spirocyclic heterocycle means a 4, 5-, 6-, 7-, or 8-membered monocyclic heterocycle ring wherein two of the substituents on the same carbon atom form a 3-, 4-, 5-, or 6-membered monocyclic ring selected from the group consisting of cycloalkyl and heterocycle, each of which is optionally substituted with 1 , 2, 3, 4, or 5 alkyl groups.
• Examples of a spiroheterocycle include, but are not limited to, 5- oxaspiro[3,4]octane and 8-azaspiro[4.5]decane.
• the monocyclic and bicyclic heterocycle groups of the present invention may contain an alkylene bridge of 1 , 2, 3, or 4 carbon atoms, linking two non-adjacent atoms of the group.
• Examples of such a bridged heterocycle include, but are not limited to, 2-azabicyclo[2.2.1]heptanyl, 2- azabicyclo[2.2.2]octanyl, 1 ,2,3,4-tetrahydro- 1 ,4-methanoisoquinolinyl, and
• the monocyclic, bicyclic, and spirocyclic heterocycle groups are connected to the parent molecular moiety through any substitutable carbon atom or any substitutable nitrogen atom contained within the group.
• C 3 alkyl is an alkyl group with three carbon atoms (i.e., n-propyl, isopropyl).
• C 3 -C 10 the members of the group that follows may have any number of carbon atoms falling within the recited range.
• a “C 3 -Cioalkyl,” for example, is an alkyl group having from 3 to 10 carbon atoms, however arranged.
• Classes of pain relieving agents that may be released from the compositions include sodium channel blockers (e.g., Nav 1.8 inhibitors, Navl .9 inhibitors, ropivacaine, bupivacaine, etc.), TRPV1 antagonists, endothelin antagonists (e.g., atrasentan, zibotentan), bradykinin antagonists, ASIC inhibitors, TrkA inhibitors, and radionuclides ( 89 Sr, 153 Sm-lexidronam, 186 Re-etidronate).
• sodium channel blockers e.g., Nav 1.8 inhibitors, Navl .9 inhibitors, ropivacaine, bupivacaine, etc.
• TRPV1 antagonists e.g., atrasentan, zibotentan
• bradykinin antagonists e.g., atrasentan, zibotentan
• bradykinin antagonists e.g., atrasentan, zi
• compositions include NSAIDS, corticosteroids, and cytokine inhibitors (e.g., inhibitors of TNF-a, IL- ⁇ , etc.).
• Classes of antimicrobial agents that may be released from the compositions include antibacterials and antifungals.
• Antibacterials include well-known agents like cephems, cephalosporins, quinolone antibiotics (e.g., ciprofloxacin, levofloxacin, etc.), macrolides (e.g., azithromycin, clarithromycin, erythromycin, etc.).
• Antifungals include fluconazole, clotrimazole, itraconazole, etc.
• Classes of anti-cancer agents that may be released from the compositions include vincristine, doxorubicin, etoposide, gemcitabine, methotrexate, SRC kinase inhibitors described by Saad in Cancer Treat Rev. 2010, 36(2) 177-84 (e.g., dasatinib, saracatinib, bosutinib).
• a bone repairing drug may be prostaglandin El , prostaglandin E2, strontium ranelate, calcitonin, parathyroid hormone, Vitamin D, or a synthetic Vitamin D analogue (e.g., ED-70), BMP-2, BMP-4, BMP-7, or platelet-derived growth factor.
• a bone repairing drug may also be an organic bisphosphonate.
• Organic bisphosphonates include, for example, alendronic acid, sodium alendronate, ibandronate, risedronate, zoledronate, zoledronic acid, etidronate, pamidronate, tiludronate, neridronate, and olpadronate.
• a bone repairing drug may also be a cathepsin K inhibitor including, for example, compounds disclosed and cited by Bromme in Expert Opin. Investig. Drugs 2009, 18(5) 585-600, (e.g., odanacatib).
• a bone repairing drug may be an estrogen or an estrogen receptor modulator including, for example, raloxifene, apeledoxifene, and lasofoxifene, including compounds described at http://en.wikipedia.org/wiki/Selective_estrogen-receptor_modulator.
• a bone repairing drug may be an androgen or an androgen receptor modulator including, for example, testosterone.
• a bone repairing drug may be an inhibitor of osteoclast proton ATPase, including, for example, compounds described by Nyman in Potential of the Osteoclast's Proton Pump as a Drug Target in Osteoporosis, Annales Universitatis Turkuensis 201 1 , e.g., SB242784, a bafilomycin (e.g., bafilomycin Al), concanamycin A, apicularen, archazolides, benzolactone enamides (salicylihalamide A, lobatamide A), FR167356, FR177995, and diphyllin.
• a bafilomycin e.g., bafilomycin Al
• concanamycin A apicularen, archazolides
• benzolactone enamides salicylihalamide A, lobatamide A
• FR167356, FR177995 FR167356, FR177995, and diphyllin.
• a bone repairing drug may be an inhibitor of HMG-CoA reductase (i.e., a statin) including, for example those described at http://en.wikipedia.org/wiki/Statin, e.g., atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitabastatin, pravastatin, rosuvastatin, and simvastatin.
• a statin including, for example those described at http://en.wikipedia.org/wiki/Statin, e.g., atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitabastatin, pravastatin, rosuvastatin, and simvastatin.
• a bone repairing drug may be an av 3integrin receptor antagonist including, for example, compounds described by Millard et al. in Integrin Targeted Therapeutics, Theranostics 201 1 , 154-188, e.g., cilengitide (EMD 121974), L000845704, SB2730005.
• a bone repairing drug may be a RANKL inhibitor such as denosumab.
• a bone repairing drug may be an EP2 agonist such as, for example, ONO- AE1-259-01 and CP-533536.
• a bone repairing drug may be an EP2/EP4 dual agonist such as, for example, those described in Bioorganic & Medicinal Chemistry Letters, 2012, 22(1), 396-401, US7,402,605, and US7,608,637.
• An exemplary dual EP2/EP4 agonist is 2-((2-((R)-2-((S,E)- 3 -hydroxy-4-(m-tolyl)but- 1 -en- 1 -yl)-5-oxopyrrolidin- 1 -yl)ethyl)thio)thiazole-4-carboxylic acid (CAS#494223-86-8).
• a bone repairing drug may be an EP4 receptor agonist including, but are not limited to, compounds disclosed in United States Patents 6,043,275, 6,462,081 ,
• EP4 agonists include, but are not limited to, CP-734432, ONO-4819 (i.e., rivenprost), AE1 -329, L-902,688.
• bone-repairing drugs included in the bone compositions are one or more of alendronic acid, sodium alendronate, ibandronate, risedronate, zoledronate, zoledronic acid, etidronate, pamidronate, tiludronate, neridronate, and olpadronate, odanacatib, raloxifene, apeledoxifene, lasofoxifene, atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitabastatin, pravastatin, rosuvastatin, simvastatin, strontium ranelate, calcitonin, parathyroid hormone, or bone morphogenic protein-2.
• bone-repairing drugs included in the bone compositions are one or more of an EP2 agonist, an EP2/EP4 dual agonist, an EP4 agonist, an organic bisphosphonate, an estrogen receptor modulator, an inhibitor of HMG-CoA reductase, and strontium ranelate.
• Bone-repairing EP4 agonist drug compounds may have also the structures set forth in formula (I), (la), or (II).
• Formula (I) refers to compounds having either ⁇ stereochemistry or a substantially equal mixture of ⁇ and a stereochemistries at the ⁇ -position of the lactam ring. Excluded are compounds having pure or substantially pure a stereochemistry at the ⁇ -position, as compounds possessing the a stereochemistry at the ⁇ -position have been found to lack appreciable activity as EP 4 receptor agonists.
• L 1 is C 3 -C 7 alkylene, C 3 -C 7 alkenylene, or C 3 -C 7 alkynylene, wherein the C 3 -C 7 alkylene, C 3 -C 7 alkenylene, or C 3 -C 7 alkynylene are each optionally substituted with 1 , 2, 3, or 4 fluoro substituents.
• L 1 is C 3 -C 7 alkylene, optionally substituted.
• L 1 is n- pentylene, n-hexylene, or n-heptylene each optionally substituted with 1 , 2, 3, or 4 fluoro substituents.
• L 1 is n-hexylene.
• L 1 is -(CH 2 ) t -G-(CH 2 ) p -; wherein t, p, and G are as defined herein.
• t and p are both 0.
• t is 0 and p is 0, 1 , 2, or 3.
• p is 0 and t is 0, l , or 2.
• L 1 is -(CH 2 ) n -G 1 -(CH 2 ) p -, wherein G 1 is as defined herein, n is 1 , 2, 3, 4, or 5 and p is 1 , 2, or 3.
• L 1 is - CH -G 2 - CH - For exam le in some embodiments
• G 2 is In other is is 2 and p is 0, 1 , 2, or 3.
• G is , p is 0, and n is 2, 3, 4, or 5.
• G 2 is , n is 3 and p is 0.
• R 1 is COOR 10 , CONR 10 R n , CH 2 OR 10 , S0 3 R 10 , SO 2 NR 10 R n , PO(OR 10 ) 2 , or tetrazol-5-yl; wherein R 10 is H, C C 4 alkyl (e.g., methyl, ethyl) or aryl (e.g., phenyl) and R 11 is H, C C 4 alkyl (e.g., methyl, ethyl), COR 12 , OR 10 , or S0 2 R 12 ; wherein R 12 is C C 4 alkyl (e.g., methyl, ethyl).
• R 1 is COOH or COOCH 3 .
• R 1 is COOH.
• L 2 is -CH 2 - or a bond. In some embodiments, L 2 is a bond.
• R 4 and R 5 are each independently H, F, CF 3 , or C C 4 alkyl (e.g., methyl, ethyl, etc.); or R 4 and R 5 togethe with the carbon to which they are attached form a C 3 -C5 cycloalkyl (e.g., cyclopropyl), , , ⁇
• R 4 and R 5 are each independently hydrogen or CH 3 .
• R 4 is C 1 -C 4 alkyl (e.g., methyl, ethyl, etc.) and R 5 is hydrogen.
• R 4 is hydrogen and R 5 is C1-C4 alkyl (e.g., methyl, ethyl, etc.). In still other embodiments, R 4 and R 5 are fluoro. In some embodiments, R 4 is methyl and R 5 is hydrogen. In other embodiments, R 4 is hydrogen and R 5 is methyl.
• the stereochemistry of the hydroxyl group on the lower chain may be either a or ⁇ or a mixture of a and ⁇ .
• R 6 is aryl or heteroaryl, each optionally substituted as described herein. In some groups of compounds, R 6 is aryl, optionally substituted as described herein. In some groups of compounds, R 6 is phenyl optionally substituted with halogen (e.g., fluoro, chloro), C C 3 haloaIkyl (e.g., CF 3 ), or -C
• halogen e.g., fluoro, chloro
• C C 3 haloaIkyl e.g., CF 3
• -C halogen
• R 6 is C 3 -C 10 alkyl, C 3 -C 10 alkenyl, C 3 -C 10 alkynyl, C 3 -C 10 haloalkyl, C 3 -C 10 haloalkenyl, or C 3 - C 10 haloalkynyl, each optionally substituted as described herein.
• R 6 is C 3 -C 10 alkyl (e.g., propyl, butyl, pentyl, octyl, etc.).
• R 6 is n-propyl, n-butyl, or n-pentyl. In a particular subgroups of compounds, R 6 is n- butyl. In other embodiments, R 6 is C 3 -C 10 alkynyl (e.g., propynyl, butynyl, pentynyl, hexynyl, etc.). In some groups of compounds, R 6 is but-2-yn-l-yl, pent-2-yn-l-yl, or hex- 2-yn-l-yl. In particular subgroups, R 6 is pent-2-yn-l-yl.
• R 6 is L 3 -R 7 , where L 3 and R 7 are as defined herein.
• L 3 is C C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene.
• the C C 6 alkylene, C 2 -C 6 alkenylene, and C 2 -C 6 alkynylene are optionally substituted with 1 , 2, 3, or 4 fluoro substituents.
• L 3 is C C 6 alkylene (e.g., propylene, butylene, pentylene, etc.), optionally substituted.
• L 3 is C
• L 3 is n-propylene, n-butylene, or n-pentylene.
• L 3 is C 2 -C 6 alkenylene (e.g., propenylene, butenylene, etc.).
• L 3 is C 2 -C 6 alkynylene (e.g., propynylene, butynylene, etc.).
• L 3 is -CH 2 -C ⁇ C-
• L 3 is -(CH 2 ) m -G 3 -(CH 2 ) q - and m, q, and G 3 are as defined herein.
• L 3 is - CH 2 m -G 4 - CH 2 - and m, , and G 4 are as
• G 4 is
• G 5 is as defined herein. In one embodiment, G 5 is tituted as described herein. In another embodiment, G 5 is 9 each optionally substituted as described herein. In another embodiment, G 5 is * O ? , optionally substituted as described herein.
• R 7 is C 3 -C 8 cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), aryl (e.g., phenyl, naphthyl), heteroaryl (e.g., thienyl, furanyl), or heterocyclyl (e.g., tetrahydrofuranyl); wherein R 7 is optionally substituted as described herein.
• R 7 is aryl, optionally substituted.
• R 7 is phenyl, optionally substituted.
• R 7 is phenyl. In some groups of compounds, R 7 is phenyl.
• R 1 is COOR 10 ;
• R 10 is H or Ci-C 4 alkyl.
• I ⁇ -R 1 is n- hexylene-COOR 10 , -(CH 2 ) n -G 2 -(CH 2 ) -COOR 10 , -(CH 2 ) n -C ⁇ C-G 2 -CO 10 , or - or
• I ⁇ -R 1 is C 3 -C 7 alkylene-R 1 and the C 3 -C 7 alkylene is optionally substituted with 1-4 fluoro substituents.
• I ⁇ -R 1 is n-pentylene-COOR 10 , n-hexylene-COOR 10 , n- heptylene-COOR 10 , etc., and R 10 is H or CH 3 .
• I ⁇ -R 1 is n-hexylene- COOH or n-hexylene-COOCH 3 .
• I ⁇ -R 1 is -(CH 2 ) n -G 2 - (CH 2 ) p -R 1 ; and G 2 is ⁇
• L l -R l is -(CH 2 ) n -G 2 - COOR 10 (i.e., p is 0), 2 is ⁇ n is 2 or 3 10 is H or CH 3 .
• L -R is .
• L -R is
• I ⁇ -R 1 is -(CH 2 ) n -G
• L l -R l is -(CH 2 ) n -G 2 - COOR 10 (i.e., p is 0), G 2 is * S f , n is 2 or 3; and R 10 is H or CH 3 .
• i n yet another embod iment,
• L -R 1 is -CH 2 -G 2 -CH 2 -COOR is H.
• L -R is -(CH 2 ) n -
• V-R 1 is
• L 4 is ⁇ and R 4 and R 5 are independently H or CH 3 .
• R 6 is C 3 -Ci 0 alkyl, C 3 -Ci 0 alkenyl, C 3 - C 10 alkynyl, C 3 -C 10 haloalkyl, C 3 -C 10 haloalkenyl, or C 3 -C 10 haloalkynyl.
• R 6 is C 3 -Ci 0 alkyl (e.g., propyl, butyl, pentyl, octyl, etc.).
• R 6 is n-propyl, n-butyl, or n-pentyl.
• R 6 is n-butyl.
• R 6 is C 3 -C 10 alkynyl (e.g., propynyl, butynyl, pentynyl, hexynyl, etc.).
• R 6 is but-2-yn- l-yl, pent-2-yn-l-yl, or hex-2-yn- l-yl.
• R 6 is pent-2-yn-l-yl.
• R 6 is aryl or heteroaryl, each optionally substituted as described herein.
• R 6 is phenyl optionally substituted with halogen (e.g., fluoro, chloro), C C 3 haloalkyl (e.g., CF 3 ), or -Ci-C 3 alkylene-Ci-C 3 alkoxy (e.g., CH 2 OCH 3 ).
• L 4 is -CH 2 -CH 2 - and R 4 and R 5 are independently H or CH 3 .
• L 4 is - C ⁇ C- and R 4 and R 5 are independently H or CH 3 .
• L 4 is ⁇ and R 4 and R 5 are independently H or CH 3 .
• Groups of compounds according to the second, third, and fourth embodiments include those where R 6 is C 3 -C 10 alkyl (e.g., propyl, butyl, pentyl, octyl, etc.), C 3 -C 10 alkynyl (e.g., propynyl, butynyl, pentynyl, hexynyl, etc.), or phenyl optionally substituted with halogen (e.g., fluoro, chloro), Ci-C 3 haloalkyl (e.g., CF 3 ), or -Ci-C 3 alkylene-Ci-C 3 alkoxy (e.g., CH 2 OCH 3 ).
• R 6 is C 3 -C 10 alkyl (e.g., propyl, butyl, pentyl, octyl, etc.), C 3 -C 10 alkynyl (e.g., propynyl, buty
• R 4 and R 5 are fluoro
• R 6 is aryl, heteroaryl, C 3 -Ci 0 alkyl, C 3 -Ci 0 alkenyl, C 3 -Ci 0 alkynyl, C 3 -Ci 0 haloalkyl, C 3 -Ciohaloalkenyl, or C 3 -Ci 0 haloalkynyl, (each optionally substituted as described herein), and L 4 is as defined herein.
• L 4 is ⁇ " ⁇ and R 6 is aryl, optionally substituted as describe herein.
• R 6 is phenyl, optionally substituted.
• R 6 is C 3 -Ci 0 alkyl, C 3 -Ci 0 alkenyl, C 3 -C 10 alkynyl, C 3 -C 10 haloalkyl, C 3 -C 10 haloalkenyl, C 3 -C 10 haloalkynyl.
• L is Ci-C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene (each optionally substituted with 1 , 2, 3, or 4 fluoro substituents), and L 4 , R 4 , R 5 , and R 7 are as defined herein.
• L is
• R 7 is C 3 -C 8 cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), aryl (e.g., phenyl, naphthyl), heteroaryl (e.g., thienyl, furanyl), or heterocyclyl (e.g., tetrahydrofuranyl); wherein R 7 is optionally substituted as described herein.
• aryl e.g., phenyl, naphthyl
• heteroaryl e.g., thienyl, furanyl
• heterocyclyl e.g., tetrahydrofuranyl
• L 3 is C C 6 alkylene (e.g., propylene, butylene, pentylene, etc.) and R 7 is phenyl, naphthyl, thienyl, or cyclohexyl, each optionally substituted.
• L 3 is C C 6 alkylene (e.g., propylene, butylene, pentylene, etc.), where the Ci-C 6 alkylene is a straight chain alkylene group, and R 7 is phenyl optionally substituted.
• L 3 is n-propylene, n-butylene, or n-pentylene and R 7 is phenyl.
• L 3 is C 2 -C 6 alkenylene (e.g., propenylene, butenylene, etc.) and R 7 is phenyl, naphthyl, thienyl, or cyclohexyl, each optionally substituted.
• L 3 is C 2 -C 6 alkynylene (e.g., propynylene, butynylene, etc.) and R 7 is phenyl, naphthyl, thienyl, or cyclohexyl, each optionally substituted.
• L 3 is -CH 2 -C ⁇ C-
• R 7 is phenyl.
• L 4 is -CH 2 -CH 2 -and R 4 and R 5 are independently H or CH 3 .
• L 4 is - C ⁇ C- and R 4 and R 5 are independently H or CH 3 .
• L 4 is ⁇ ⁇ " and R 4 and R 5 are independently H or CH 3 .
• Groups of compounds according to the second, third, and fourth embodiments include those where L 3 is C 2 -C 6 alkylene (e.g., propylene, butylene, pentylene, etc.), C 2 -C 6 alkenylene (e.g., propenylene, butenylene, etc.), or C 2 -C 6 alkynylene (e.g., propynyl, butynyl, etc.), and R 7 is phenyl, naphthyl, thienyl, or cyclohexyl, each optionally substituted.
• L 3 is C 2 -C 6 alkylene (e.g., propylene, butylene, pentylene, etc.), C 2 -C 6 alkenylene (e.g., propenylene, butenylene, etc.), or C 2 -C 6 alkynylene (e.g., propynyl, butynyl, etc.)
• R 7 is
• L 3 is -(CH 2 ) m -G 3 -(CH 2 ) q -, -(CH 2 ) m -G 4 -(CH 2 ) q -, or -G 5 -C ⁇ C-;
• L 4 , G 3 , G 4 , G 5 , R 4 , R 5 , R 7 , m, and q are as defined herein.
• L is ⁇ and R 4 and R 5 are independently H or CH 3 .
• L 3 is -G 5 -C ⁇ C-
• G 5 is
• R 7 is C 3 -C 8 cycloalkyl (e.g., cyclopropyl, cyclopentyl, cyclohexyl), aryl (e.g., phenyl, naphthyl), heteroaryl (e.g., thienyl, furanyl), or heterocyclyl (e.g., tetrahydrofuranyl); wherein R 7 is optionally substituted as described herein.
• R 2 and R 3 are each hydrogen; R 4 and R 5 are independently H or C C 4 alkyl; R 6 is C 3 -C 10 alkyl, C 3 -C 10 alkynyl, or L 3 -R 7 ; L 3 is C C 6 alkylene or C 2 -C 6 alkynylene; wherein the Ci-C 6 alkylene and C 2 -C 6 alkynylene are optionally substituted with 1 , 2, 3, or 4 fluoro substituents; and R 7 is aryl, wherein R 7 is optionally substituted with 1 , 2, 3, or 4 substituents selected from the group consisting of C C 4 alkyl, C C 3 haloalkyl, cyano, halogen, Q-Qalkoxy, Q-Qhaloalkoxy, and -C C 3 alky lene-C i -C 3 alkoxy .
• L is -C(R 2 ) 2 -C(R 3 ) 2 - wherein R 2 and R 3 are each H, CH 3 , fluoro, or chloro; R 4 and R 5 are each independently H, F, CF 3 , or C C 4 alkyl; or R 4 and R 5 together with the carbon to which they are attached form a C 3 -C 5 cycloalkyl; R 6 is aryl, C 3 - Ci 0 alkyl, C 3 -Ci 0 alkenyl, C 3 -Ci 0 alkynyl, C 3 -Ci 0 haloalkyl, C 3 -Ci 0 haloalkenyl, C 3 - C 10 haloalkynyl, or L 3 -R 7 ; L 3 is C C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene wherein the Ci-C 6 alkylene, C 2 -C 6 alkeny
• L 4 is ⁇ - ⁇ R 4 and R 5 are independently H or C C 4 alkyl;
• R 6 is C 3 -C 10 alkyl, C 3 -C 10 alkenyl, C 3 -Ci 0 alkynyl, C 3 -Ci 0 haloalkyl, C 3 -Ci 0 haloalkenyl, C 3 -Ci 0 haloalkynyl, or L 3 -R 7 ;
• L 3 is C C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene; wherein the C C 6 alkylene, C 2 - C 6 alkenylene, and C 2 -C 6 alkynylene are optionally substituted with 1 , 2, 3, or 4 fluoro substituents;
• R 7 is aryl, wherein R 7 is optionally substituted with 1 , 2, 3, or 4 substituents selected from the
• G 2 is R 10 is H or C C 4 alkyl; R 4 and R 5 are independently H or CH 3 ; L 3 is ethynylene, propynylene, or butynylene; and R 6 is phenyl or C C 6 alkyl, wherein the phenyl is optionally substituted with 1 , 2, 3, or 4 substituents selected from the group consisting of Ci-C 4 alkyl, Ci-C 3 haloalkyl, cyano, halogen, C C 3 alkoxy, Q-Qhaloalkoxy; and -C 1 -C 3 alkylene-C 1 -C 3 alkoxy.
• L l -R l is C 3 -C 7 alkylene-R 1 ; -R 1 is -( ⁇ 2 ) ⁇ -0 2 -( ⁇ 2 ) ⁇ - ⁇ , wherein n is 2 or 3 and p is 0; G 2
• R 1 is COOR 10 ; and R 10 is H or C C 4 alkyl.
• R 4 and R 5 are independently H or CH 3 ;
• R 6 is C 3 -Ci 0 alkyl, C 3 -Ci 0 alkynyl, or L 3 -R 7 ;
• L 3 is C
• R 7 is aryl, wherein R 7 is optionally substituted with 1 , 2, 3, or 4 substituents selected from the group consisting of Ci-C 4 alkyl, Ci-C 3 haloalkyl, cyano, halogen, Ci-C 3 alkoxy, Ci-C 3 haloalkoxy, and -C C 3 alkylene-C C 3 alkoxy.
• L 1 is C 3 -C 7 alkylen -
• L 1 is C 3 -C 7 alkylene or -(CH 2 ) n -G z -; n is 2 or 3; G z is " ⁇ — V Or 3 ⁇ 4 S f ; R 6 is propyl, butyl, pentyl, propynyl, butynyl, pentynyl, hexynyl, or L 3 -R 7 ; L 3 is propylene, butylene, pentylene, propynylene, or butynylene; and R 7 is phenyl or phenyl optionally substituted.
• L 1 is C 3 -C 7 alkylene and R 6 is propyl, butyl, pentyl, propynyl, butynyl, pentynyl, or hexynyl.
• L 1 is C 3 -C 7 alkylene and R 6 is L 3 -R 7 ;
• L 3 is propylene, butylene, pentylene, propynylene, or butynylene; and
• R 7 is phenyl or phenyl optionally substituted.
• L 1 is -(CH 2 ) n -G 2 -, wherein n is 2 or 3; pentynyl, or he is -(CH 2 ) n -G 2 -, wherein n is 2 or 3; G 2 is ; L 3 is propylene, butylene, pentylene, propynylene, or butynylene; and R 7 is phenyl or phenyl optionally substituted.
• L 1 is n-hexylene or -(CH 2 ) n -G 2 -, wherein n is 2 or 3; G 2 is COOR 10 ; R 10 is H or CH 3 ; R 6 is n-butyl, but-2-yn-l- yl, pent-2-yn-l-yl, hex-2-yn-l-yl, or L 3 -R 7 ; L 3 is n-propylene, n-butylene, or n-pentylene or -CH 2 -C ⁇ C-; and R 7 is phenyl or phenyl optionally substituted.
• L 1 is n-hexylene; R 1 is COOR 10 ; R 10 is H or CH 3 ; and R 6 is n-butyl, but-2- yn-l-yl, pent-2-yn-l-yl, or hex-2-yn-l-yl.
• L 1 is n- hexylene; R 1 is COOR 10 ; R 10 is H or CH 3 ; and R 6 is L 3 -R 7 ; L 3 is n-propylene, n-butylene, n-pentylene or -CH 2 -C ⁇ C-; and R 7 is phenyl or phenyl optionally substituted.
• L 1 is -(CH 2 ) n -G 2 -, wherein n is 2 or 3; G 2 is or
• R 1 is COOR 10 ;
• R 10 is H or CH 3 ; and
• R 6 is n-butyl, but-2-yn-l-yl, pent-2-yn-
• R 6 is C 3 -C 10 alkyl, C 3 -C 10 alkenyl, C3-C 10 alkynyl, C 3 -C 10 haloalkyl, C 3 -C 10 haloalkenyl, or C 3 - Ciohaloalkynyl.
• L 1 is C 3 -C 7 alkylene, wherein the alkylene is optionally substituted with 1 , 2, 3, or 4 fluoro substituents.
• R 6 is C 3 -C 10 alkyl, C 3 -C 10 alkenyl, or C 3 -C 10 alkynyl; and L 1 is C 3 -C 7 alkylene.
• R 6 is C 3 -C 10 alkyl, C 3 - Ci 0 alkenyl, or C 3 -Ci 0 alkynyl; and L 1 is -(CH 2 ) n -G 2 -(CH 2 ) p -, wherein n is 2 or 3 and p is
• R 6 is L 3 -R 7 ;
• L 3 is C C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene; wherein the C C 6 alkylene, C 2 -C 6 alkenylene, and C 2 -C 6 alkynylene are optionally substituted with 1 , 2, 3, or 4 fluoro substituents;
• R 7 is aryl, wherein R 7 is optionally substituted with 1 , 2, 3, or 4 substituents selected from the group consisting of Ci-C 4 alkyl, Ci-C 3 haloalkyl, cyano, halogen, C C 3 alkoxy, C C 3 haloalkoxy, and -C 1 -C 3 alkylene-C 1 -C 3 alkoxy.
• L 1 is C 3 -C 7 alkylene, wherein the C 3 -C 7 alkylene is optionally substituted with 1, 2, 3, or 4 fluoro substituents.
• R 6 is L 3 -R 7 ;
• L 3 is Ci-C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene;
• R 7 is aryl or optionally substituted aryl;
• L 1 is C 3 -C 7 alkylene.
• R 6 is L 3 -R 7 ;
• L 3 is C C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene;
• R 7 is phenyl or phenyl optionally substituted; and
• L 1 is C 3 -C 7 alkylene.
• R 6 is L 3 -R 7 ;
• L 3 is C 1 -C 6 alkylene, C 2 - C 6 alkenylene, or C 2 -C 6 alkynylene;
• R 7 is aryl;
• L 1 is -(CH 2 ) n -G 2 -(CH 2 ) p -, wherein n is 2 or 3, and p is 0; and
• G 2 is ⁇ ⁇ or ⁇ ⁇ . i n still another subgroup R 6 is
• L 3 -R 7 L 3 is C C 6 alkylene, C 2 -C 6 alkenylene, or C 2 -C 6 alkynylene; R 7 is phenyl or phenyl optionally substituted; and L 1 is -(CH 2 ) n -G 2 -(CH 2 ) p -, wherein n is 2 or 3, and p is 0; and
• L 1 is C 3 -C 7 alkylene, wherein the C 3 -C 7 alkylene is optionally substituted with 1 , 2, 3, or 4 fluoro substituents.
• G 2 is optionally substituted with 1 , 2, or 3 substituents selected from the group consisting of C C 4 alkyl, C C 3 haloalkyl, cyano, halogen, C C 3 alkoxy, and Ci-C 3 haloalkoxy.
• L 1 is -(CH 2 ) n -G 2 -(CH 2 ) p -
• n 2 or 3
• p is 0, and G 2 is or .
• G 1 is O, C(O), S, S(O), S(0) 2 , or NR 8 ; wherein R 8 is H, C C 4 alkyl, or C C 4 alkylcarbonyl; wherein G 2 is optionally substituted with 1 , 2, or 3 substituents selected from the group consisting of C 1 -C 4 alkyl, C C 3 haloalkyl, cyano, halogen, C C 3 alkoxy, and Ci-C 3 haloalkoxy;
• R 1 is COOR 10 , CONR 10 R n , CH 2 OR 10 , S0 3 R 10 , SO 2 NR 10 R n , PO(OR 10 ) 2 , or tetrazol-5-yl;
• R 10 is H, Ci-C 4 alkyl, or aryl
• R 11 is H, C1-C4 alkyl, COR 12 , OR 10 , or S0 2 R 12 ;
• R 12 is C1-C4 alkyl
• R 13 at each occurrence, is independently H or C C 4 alkyl
• R 4 and R 5 are each independently H, F, CF 3 , or C C 4 alkyl; or R 4 an R 5 together with the carbon to which they are attached form a C 3 -C 5 cycloalkyl, ,
• R 6 is aryl, heteroaryl, C 3 -C 10 alkyl, C 3 -C 10 alkenyl, C 3 -C 10 alkynyl, C 3 - C 10 haloalkyl, C 3 -C 10 haloalkenyl, C 3 -C 10 haloalkynyl, or L 3 -R 7 ; wherein the aryl and heteroaryl are optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C 1 -C 4 alkyl, C C 3 haloalkyl, cyano, halogen, C C 3 alkoxy, C C 3 haloalkoxy; and -Ci-C 3 alkylene-Ci-C 3 alkoxy; and wherein the C 3 -Ci 0 alkyl, C 3 -Ci 0 alkenyl, C 3 - C 10 alkynyl, C 3 -C 10 haloalkyl, C 3 -C
• G 3 is O, C(O), S, S(O), S(0) 2 , or NR 9 ; wherein R 9 is H, C C 4 alkyl, or C C 4 alkylcarbonyl;
• G 4 is optionally substituted with 1 , 2, or 3 substituents selected from the group consisting of C C 4 alkyl, C C 3 haloalkyl, cyano, halogen, C C 3 alkoxy, and C C 3 haloalkoxy; optionally substituted with 1 , 2, or 3 substituents selected from the group consisting of Ci-C 4 alkyl, Ci-C 3 haloalkyl, cyano, halogen, Ci-C 3 alkoxy, and Ci-C 3 haloalkoxy;
• R 7 is C 3 -C 8 cycloalkyl, aryl, heteroaryl, or heterocyclyl; wherein R 7 is optionally substituted with 1 , 2, 3, or 4 substituents selected from the group consisting of C C 4 alkyl, C C 3 haloalkyl, cyano, halogen, Q-Qalkoxy, Q-Qhaloalkoxy, and -C C 3 alkylene-Ci-C 3 alkoxy; and
• r is O or l .
• R 1 is COOR 10 ;
• R 10 is H or C C 4 alkyl;
• R 4 and R 5 are each independently H or Ci-C 4 alkyl;
• R 6 is C 3 -C 10 alkyl, C 3 -C 10 alkenyl, C 3 -C 10 alkynyl, or L 3 -R 7 ;
• L 3 is C
• R 5 are each independently H or C 1 -C 4 alkyl;
• R 6 is C 3 -C 10 alkyl, C 3 -C 10 alkenyl, C 3 - C 10 alkynyl, or L 3 -R 7 ;
• L 3 is C C 6 alkylene, C 2 -C 6 alkynylene, or C 2 -C 6 alkynylene; and
• R 7 is aryl, optionally substituted as described herein.
• R 1 is C 3 -C 7 alkylene or -(CH 2 ) n -G 2 -(CH 2 ) p - wherein n is 2 or 3, p is 0; G 2 or S ;
• R 1 is COOR 10 ;
• R 10 is H or C C 4 alkyl;
• R 4 and R 5 are each independently H or C C 4 alkyl;
• R 6 is C 3 -C 10 alkyl, C 3 - C 10 alkynyl, or L 3 -R 7 ;
• L 3 is C C 6 alkylene, C 2 -C 6 alkynylene, or C 2 -C 6 alkynylene;
• R 7 is aryl, optionally substituted as described herein.
• bone-repairing EP4 agonist drug compounds are selected from the group consisting of:
• the invention also provides for bone compositions that include combinations of any of the drugs or classes of drugs described herein.
• one or more drugs that activate osteoblasts may be combined with one or more drugs that inhibit osteoclasts.
• multiple drugs that either activate osteoblasts or inhibit osteoclasts may be combined together.
• bone compositions may include an EP4 agonist with any one or more of the following: a bisphosphonate; a cathepsin K inhibitor; an estrogen or an estrogen receptor modulator; calcitonin; an inhibitor of osteoclast proton ATPase; an inhibitor of HMG-CoA reductase (i.e., a statin); an av 3integrin receptor antagonist; a RANKL inhibitor such as denosumab; a bone anabolic agent, such as parathyroid hormone; a bone morphogenic protein (e.g., BMP-2, BMP-4, BMP-7); Vitamin D or a synthetic Vitamin D analogue such as ED-70; an androgen or an androgen receptor modulator; an activator of Wnt/p-catenin signaling (e.g. a GSK-3 inhibitor, a sclerostin antagonist, a SOST inhibitor); bortezomib; strontium ranelate; platelet
• an EP4 agonist is combined with one or more bisphosphonates selected from alendronic acid, sodium alendronate, ibandronate, risedronate, zoledronate, zoledronic acid, etidronate, pamidronate, tiludronate, neridronate, and olpadronate.
• an EP4 agonist is combined with one or more of raloxifene, apeledoxifene, and lasofoxifene.
• an EP4 agonist is combined with a bone morphogenic protein, e.g., BMP-2, BMP-4, or BMP-7.
• a bone morphogenic protein e.g., BMP-2, BMP-4, or BMP-7.
• BMP-2 bone morphogenic protein
• BMP-4 bone morphogenic protein
• one combination includes CP- 734432 with either BMP-2 or BMP-7.
• Another combination includes ONO-4819 (rivenprost) with BMP-2 or BMP-7.
• Yet another combination includes AE 1 -329 with BMP-2 or BMP-7.
• Still another combination includes L-902,688 with BMP-2 or BMP-7.
• a further combination includes 7-((i?)-3,3-difluoro-5-((35',45 , ,£ ' )-3-hydroxy-4-methylnon- l-en-6-yn-l -yl)-2-oxopyrrolidin-l -yl)heptanoic acid with BMP-2 or BMP-7.
• Another combination includes 7-((i?)-2-((35',45 , ,£ ' )-3-hydroxy-4-methylnon- 1 -en-6-yn- 1 -yl)-5- oxopyrrolidin-l -yl)heptanoic acid with BMP-2 or BMP-7.
• an EP4 agonist is combined with strontium ranelate.
• an EP4 agonist is combined with an EP2 agonist.
• an EP4 agonist is combined with a statin such as, for example, atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitabastatin, pravastatin, rosuvastatin, and simvastatin.
• a statin such as, for example, atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitabastatin, pravastatin, rosuvastatin, and simvastatin.
• a bisphosphonate is combined with an estrogen receptor modulator.
• an estrogen receptor modulator For example, one or more of alendronic acid, sodium alendronate, ibandronate, risedronate, zoledronate, zoledronic acid, etidronate, pamidronate, tiludronate, neridronate, and olpadronate is combined with one or more of raloxifene, apeledoxifene, and lasofoxifene.
• a bisphosphonate and/or an estrogen receptor modulator is combined with a statin. Any of the foregoing classes or compounds could, alternatively or in addition to, be combined with strontium ranelate and/or a bone morphogentic protein.
• the EP4 agonist may be a compound of formula (I) or any other EP4 agonist according to the description contained herein.
• Exemplary preferred EP4 agonists include CP-734432, ONO-4819 (i.e., rivenprost), AE1 -329, L-902,688, 7-((i ⁇ -3,3-difluoro-5-((3S,4S,£)-3-hydroxy-4- methylnon-l-en-6-yn- l-yl)-2-oxopyrrolidin-l -yl)heptanoic acid, and 7-((R)-2-((3S,4S,E)- 3-hydroxy-4-methylnon- 1 -en-6-yn- 1 -yl)-5-oxopyrrolidin- 1 -yl)heptanoic acid.
• resolution examples are, for example, (i) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography, followed by liberation of the optically pure product; or (ii) separation of the mixture of enantiomers or diastereomers on chiral chromatographic columns.
• Geometric isomers may exist in the present compounds. All various geometric isomers and mixtures thereof resulting from the disposition of substituents around a carbon-carbon double bond, a carbon-nitrogen double bond, a cycloalkyl group, or a heterocycle group are contemplated. Substituents around a carbon-carbon double bond or a carbon-nitrogen bond are designated as being of Z or E configuration and substituents around a cycloalkyl or a heterocycle are designated as being of cis or trans configuration.
• the structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms.
• compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of this invention.
• Such compounds are useful, for example, as analytical tools, probes in a biological assay, or as EP 4 receptor agonists.
• Also contemplated as part of the invention are compounds formed by synthetic means or formed in vivo by biotransformation or by chemical means.
• certain compounds of the invention may function as prodrugs that are converted to other compounds of the invention upon administration to a subject.
• Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3 d ed.), John Wiley & Sons, NY (1999), which is incorporated herein by reference in its entirety.
• an optically active form of a compound When an optically active form of a compound is required, it may be obtained by carrying out one of the procedures described herein using an optically active starting material (prepared, for example, by asymmetric induction of a suitable reaction step), or by resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic resolution).
• an optically active starting material prepared, for example, by asymmetric induction of a suitable reaction step
• resolution of a mixture of the stereoisomers of the compound or intermediates using a standard procedure (such as chromatographic separation, recrystallization or enzymatic resolution).
• a pure geometric isomer of a compound when a pure geometric isomer of a compound is required, it may be obtained by carrying out one of the above procedures using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as
• ⁇ -lactams also known as oxopyrrolidines or pyrrolidinones
• HPLC High performance liquid chromatography
• HPLC high performance liquid chromatography
• TLC Thin layer chromatography
• ACN is acetonitrile
• BBr 3 is boron tribromide
• Bn is benzyl
• BnNH 2 is benzylamine
• BSA is bovine serum albumin
• CH 2 C1 2 is dichloromethane
• CHC1 3 is chloroform
• CDCI 3 is deuterochloroform
• CSA camphorsulfonic acid
• DCC is AvV'-dicyclohexylcarbodiimide
• DME is 1 ,2-dimethoxyethane
• DMF is N,N-diniethylformamide
• DMP is 2,2-dimethoxypropane (also called, acetone dimethyl acetal);
• DMSO is dimethyl sulfoxide
• DBU is l ,8-diazabicyclo[5.4.0]undec-7-ene
• DIA is diisopropylamine
• DMAP is 4-dimethylaminopyridine
• EDC/EDAC is N-(3-dimethylaminopropyl)-N , -ethylcarbodiimide hydrochloride
• EDTA is ethylenediaminetetraacetic acid
• EE is ethoxyeth- 1 -yl
• EIA enzyme immunoassay
• Et is ethyl
• EtOAc is ethyl acetate
• EtOH is ethanol
• Et,N is triethylamine
• HC1 is hydrogen chloride
• HOBt is 1 -hydroxybenzotriazole
• Me is methyl
• MeOH is methanol
• MTBE is methyl tert-butyl ether
• NaOMe is sodium methoxide
• nBuLi or n-BuLi is «-butyllithium
• NFSi is N-fluorobenzenesulfonimide
• NHS is N-hydroxysuccinimide
• NMP is 1 -methyl-2-pyrrolidinone
• PG is a protecting group
• Ph is phenyl
• Pd(PPh 3 ) 4 is /e/ra zs(triphenylphosphine)palladium;
• PhMe is toluene;
• rt is room temperature
• TBAF is tetrabutylammonium fluoride
• TBS or TBDMS is tert-butyldimethylsilyl
• tBu or t-Bu is tert-butyl
• TEA is triethylamine
• TFA is trifluoroacetic acid
• THF is tetrahydrofuran
• TMS is trimethylsilyl
• Tris-HCl is 2-amino-2-(hydroxymethyl)-l ,3-propanediol hydrochloride
• a ⁇ -lactam scaffold common to various compounds used in the present invention may be derived from the difluorooxopyrrolidinyl intermediate, (i?)-3,3-difluoro- 5-(hydroxymethyl)pyrrolidin-2-one ((R)-8), which may be prepared from commercially available (i?)-(+)-5-oxopyrrolidine-2-carboxylic acid (D-pyroglutamic acid) (1) as illustrated in Scheme 1.
• D-pyroglutamic acid (1) may undergo acid-catalyzed esterification in an alcohol solvent, such as methanol, as illustrated in Step A.
• the resulting ester intermediate (2) may be reduced with sodium borohydride in a solvent, such as THF, to the alcohol intermediate (i?)-5-(hydroxymethyl)pyrrolidin-2-one (3) as shown for Step B.
• the followings Steps C, D, E, F, and G may be carried out according to the procedures described in US 2009/0275537.
• Simultaneous protection of the alcohol and amide groups of intermediate 3 by the acid-catalyzed addition of 2,2-dimethoxypropane provides protected intermediate 4.
• Step D and E Subsequent repeat stepwise deprotonation followed by addition of electrophilic fluorine using NFSi (Steps D and E) affords the ⁇ , ⁇ - difluoropyrrolidone intermediate 6.
• Annulation (Step G) is achieved with the use of a base, such as triethylamine, to provide (i?)-3,3-difluoro-5-(hydroxymethyl)pyrrolidin-2-one ((R)-8).
• Step A comprising the addition of a solution comprising sec-butyllithium in (about 1.1 molar equivalents of sec-butyllithium) to a solution comprising 4 (limiting reagent) in THF at - 78°C, stirring for about an hour at -78 °C, subsequent addition of a solution comprising NFSi (about 1.1 molar equivalents of NFSi), stirring for about another hour at - 78 °C, addition of a solution comprising LiHMDS (about 1.1 molar equivalents), stirring for about another hour at
• R 14 is hydrogen or an oxygen protecting group.
• R 15 is hydrogen or a nitrogen protecting group.
• Compounds of the present invention, (I) may be prepared from 8 or protected 8, for example, by a process that comprises first installing the upper chain with a nitrogen-carbon bond forming reaction (using 8 or an O-protected 8), wherein the nitrogen atom of the ⁇ -lactam ring of 8 forms a covalent bond with the appropriate upper chain carbon atom to provide the corresponding 8 + upper chain intermediate shown in Scheme 2.
• the nitrogen-carbon forming reaction comprises an alkylation reaction between 8 or an oxygen-protected analog of 8 and an alkylating agent comprising the upper chain moiety and a leaving group as illustrated in Scheme 2A.
• the alkylating agent is an alkyl halide such as an alkyl iodide, alkyl bromide, or alkyl triflate. In other aspects of the present invention, the alkylating agent is an allyl bromide. In other aspects of the present invention, the alkylating agent is a propargyl halide such as a propargyl bromide.
• LG is, for example, bdo, bromo, chloro, trifluoromethanesulfonyl, methanesulfonylate toluenesulfonylate, or 4-nitrobenzenesulfonylate.
• R 3 is hydrogen or an oxygen protecting grou p.
• the installation of the upper chain may be followed by a process that comprises installation of the lower chain by way of a carbon-carbon bond forming reaction, wherein the hydroxymethyl group carbon atom attached to the ⁇ -position of the lactam ring of intermediate 8 + upper chain forms a covalent bond (carbon-carbon single, double, or triple bond) with the appropriate lower chain carbon atom to provide the corresponding compound (I).
• the intermediate 8 + upper chain (directly from the alkylation reaction or its O-protected analog having undergone subsequent deprotection) is oxidized to the corresponding aldehyde intermediate, which may be subsequently subjected to Horner- Wadsworth- Emmons reaction conditions in the presence of a ⁇ -keto phosphonate ester coupling partner to, after subsequent reduction of the resulting ketone to the corresponding alcohol, provide compounds (I) of the present invention, wherein L 4 is a carbon-carbon double bond, as illustrated in Scheme IB.
• compounds of the present invention, (I) may be prepared from 8 or protected 8, for example, by a process that comprises first installing the lower chain with a carbon-carbon bond forming reaction (using 8 or an N-protected 8), wherein the hydroxymethyl group carbon atom attached to the ⁇ -position of the lactam ring of intermediate 8 forms a covalent bond (carbon-carbon single, double, or triple bond) with the appropriate lower chain carbon atom to provide the corresponding 8 + lower chain intermediate shown in Scheme 2.
• the installation of the lower chain may be followed by a process that comprises installation of the upper chain by way of nitrogen-carbon bond forming reaction, wherein the nitrogen atom of the ⁇ -lactam ring of 8 + lower chain forms a covalent bond with the appropriate upper chain carbon atom to provide the corresponding compound (I).
• the synthetic route to a compound (I) comprises a process wherein certain intermediates 8 + upper chain may undergo chemical reaction or a series of chemical reactions, which are known in the art or disclosed herein, that chemically modify the upper chain such that chemical installation and/or modification of the lower chain is facilitated.
• the synthetic route to a compound (I) comprises a process wherein a certain intermediate 8 + upper chain may undergo chemical reaction or a series of chemical reactions, which are known in the art or disclosed herein, that chemically modify the upper chain such that at least one particular functional group or other structural feature not incorporated into said intermediate is incorporated into the structure of invention compound (I).
• the synthetic route to a compound (I) comprises a process wherein certain intermediates 8 + lower chain may undergo chemical reaction or a series of chemical reactions, which are known in the art or disclosed herein, that chemically modify the lower chain such that chemical installation and/or modification of the upper chain is facilitated.
• the synthetic route to a compound (I) comprises a process wherein a certain intermediate 8 + lower chain may undergo chemical reaction or a series of chemical reactions, which are known in the art or disclosed herein, that chemically modify the lower chain such that at least one particular functional group or other structural feature not incorporated into said intermediate is incorporated into the structure of invention compound (I).
• the synthesis may comprise a sequence of steps as shown in Scheme 2C.
• Omission of the hydrogenation step of Scheme 2C may provide compounds of Formula (I) wherein L 4 is a carbon-carbon double bond and wherein various R 4 and R 5 may be incorporated.
• R 4 and R 5 are determined by the starting ketone used in the chemical route sequence.
• Some ketones that may be utilized for this purpose and are commercially available include butan-2-one, pentan-2-one, 3-methyl-2-butanone (Aldrich), cyclopropyl methyl ketone (Aldrich), cyclobutyl methyl ketone (Aldrich), and 1 -cyclopentyl-ethanone (Aldrich).
• Starting ketones and substituted acetylenes may also be available according to published procedures or methods well known to those skilled in the art.
• Synthetic routes utilized to prepare compounds of the present invention typically proceed through a carbon-carbon double bond formation (olefination) step to install the compound's lower chain.
• the olefination may be accomplished by the interaction of an appropriate aldehyde intermediate with an appropriate nucleophilic carbanion species.
• Such methods may include Wittig reactions, wherein the nucleophilic carbanion species is an appropriate organic phosphonium ylide.
• Another carbon-carbon bond forming reaction that may be employed is a Horner- Wadsworth-Emmons reaction, wherein the coupling partner with the aldehyde is an appropriate organic phosphonate carbanion.
• Aldehydes that may be used in the olefination step involved in preparation of compounds of the present invention include, but are not limited to, intermediates 13a-f, which can be generally prepared from (i?)-3,3-difluoro-5-(hydroxymethyl)pyrrolidin-2- one ((R)-8), as shown in Scheme 3.
• intermediate (R)-8 may be protected (Step H) by reacting with ethyl vinyl ether (EVE) in the presence of TFA or teri-butyldimethylsilyl chloride (TBDMSC1) in the presence of a base, such as imidazole, to provide the EE- protected or TBS-protected species (9), respectively.
• EVE ethyl vinyl ether
• TBDMSC1 teri-butyldimethylsilyl chloride
• a base such as imidazole
• Aldehyde intermediate 13f may alternatively be acquired by the hydrogenation of protected alcohol intermediates lid or lie to llf or the unprotected alcohol intermediates 12d or 12e to 12f, followed by the subsequent deprotection (for llf) and controlled oxidation to 13f.
• One hydrogenation reaction example is illustrated in Scheme 4. Palladium-catalyzed reduction of the internal carbon-carbon double bond of intermediate 12e (Scheme 4) to provide alcohol intermediate 12f followed by the controlled oxidation of the alcohol affords aldehyde intermediate 13f as illustrated in Scheme 3, Step K.
• reaction mixture was subsequently heated to 95 °C for one hour, cooled to room temperature, treated with triethylamine (5 mL), and stirred for 5 minutes.
• the mixture was then diluted with hexanes-ethyl acetate (500 mL, 1 :3 v/v) and washed sequentially with a 50% aqueous solution of sodium chloride and a saturated aqueous solution of sodium chloride.
• the organic phase was dried over sodium sulfate, filtered, and concentrated.
• reaction mixture was then treated with a solution consisting of N-fluorobenzenesulfonimide (56.6 g, 167 mmol, NFSi, from Oakwood Chemical) in THF (300 mL) with steady addition over 30 minutes, and the resulting mixture was stirred for 16 hours, warming to room temperature.
• a saturated aqueous solution of ammonium chloride was added to the reaction mixture.
• the organic material was extracted twice with ethyl acetate. The organic layer was washed with a 50% aqueous solution of sodium chloride, followed by a saturated solution of sodium chloride, and dried over sodium sulfate, filtered, and concentrated.
• the residue was redissolved in ethyl acetate (200 mL) and treated with heptane (200 mL), causing the formation of a white precipitate.
• the precipitate was filtered and washed with 50% ethyl acetate in heptane.
• the combined filtrate was concentrated.
• the residue was dissolved in ethyl acetate (200 mL) and treated with heptane (200 mL), forming a second precipitate.
• the second precipitate was filtered and washed with 50% ethyl acetate in heptane.
• the filtrate was concentrated and the residue (31 g) was purified by silica gel chromatography.
• reaction mixture was then treated with a solution consisting of N-fluorobenzenesulfonimide (17.5 g, 55.4 mmol) in THF (100 mL) with steady addition over ten minutes. The resulting mixture was stirred for 30 minutes. Lithium Ws(trimethylsilyl)amide (10.0 mL, 10 mmol) was added, and the reaction stirred for 16 hours, warming to room temperature. To the reaction mixture was added a 50% aqueous solution of ammonium chloride. The organic material was extracted with ethyl acetate-heptane (5: 1).
• the organic layer was washed sequentially with a 50% aqueous solution of sodium chloride, water, and a saturated solution of sodium chloride, then dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography.
• the resulting reaction mixture was stirred for one hour and was subsequently treated with a mixture consisting of N-fluorobenzene sulfonimide (35 g, 1 1 1 mmol, NFSi, from Oakwood) in THF (100 mL) with steady addition over five minutes.
• the resulting reaction mixture was stirred for another hour, after which time a lithium Ws(trimethylsilyl)amide solution (LiHMDS, 1 10 mL, 1 10 mmol, 1.0 M in THF, from Sigma Aldrich) was added dropwise over five minutes.
• LiHMDS lithium Ws(trimethylsilyl)amide solution
• the resulting reaction mixture was stirred for another hour, after which time a mixture consisting of NFSi (34.4 g, 109 mmol) in THF (100 mL) was added over five minutes.
• the resulting reaction mixture was stirred for two hours, after which time was added lithium bis(trimethylsilyl)amide (40 mL, 40 mmol, 1M in THF) to the -78 °C reaction mixture, which was subsequently stirred for 30 minutes.
• the cooling bath was removed and a saturated aqueous solution of ammonium chloride added.
• the reaction mixture was allowed to warm to room temperature, and the organic material was extracted with ethyl acetate.
• the organic layer was sequentially washed with water, a 50% saturated aqueous solution of sodium chloride, and a saturated solution of sodium chloride, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography.
• reaction mixture was diluted with ethyl acetate (150 mL) and washed with a saturated aqueous solution of sodium bicarbonate (10 mL) and brine (5 mL) before being dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography.
• the reaction mixture was stirred for five days and was quenched with a saturated solution of ammonium chloride (200 mL).
• the organic material was extracted with diethyl ether (3x300 mL).
• the combined organic phase was washed with water (100 mL) and brine (2x50 mL) before drying over sodium sulfate and concentrating to a dark brown oil.
• the residue was purified by silica gel chromatography.
• Carboxylic esters 14 may be commercially available or prepared from commercially-available starting materials as shown in Schemes 7a-g.
• the numbering system comprising various numerical, lower-case alphabetical, and lower-case Roman numeral descriptors, for intermediates comprising component B, such as carboxylic esters 14, ⁇ -keto phosphonate esters 15, NHS esters 18, amides 19, carboxylic acids 20, and (S)- 3-(B-carbonyl)-4-benzyloxazolidin-2-ones 21 found in Schemes, Tables, and Examples herein shall be interpreted as follows:
• R 18 is an NHS ester; R 4 and R 5 are hydrogen (e.g. 14aa), no lower-case
• both R 4 and R 5 are identical C C 4 alkyl, or R 4 and R 5 with the carbon to which they are bound form a C3-C5 cycloalkyl.
• This descriptor does not take into account embodiments for which both R 4 and R 5 are C1-C4 alkyl that are different one from another.
• a carboxylic ester, 14(a-o)a or 14(a-o)b/c(i-viii), may be prepared in two steps from commercially available diethyl malonate or an appropriate commercially available diethyl 2-(C C 4 alkyl) malonate starting material. Reaction of the malonate starting material with an appropriate lithium amide base, such as LDA or LiHMDS, or an appropriate hydride base, such as sodium hydride, or alkoxide base, such as sodium ethoxide, followed with an appropriate alkylating agent R 6 -X x , as illustrated in Scheme 7a, Step A, affords the corresponding 2-R 6 -substituted diethyl malonate 16.
• an appropriate lithium amide base such as LDA or LiHMDS
• an appropriate hydride base such as sodium hydride
• alkoxide base such as sodium ethoxide
• Step B provides the corresponding carboxylic ester intermediate 14, wherein both R 4 and R 5 are hydrogen, or wherein one of R 4 and R 5 is a C 1 -C 4 alkyl group (alkyl groups (i) through (viii) represent methyl, ethyl, «-propyl, 2-propyl, «-butyl, iso- butyl, sec-butyl, and tert-bvXy ⁇ , respectively) and the other is a hydrogen.
• alkyl groups (i) through (viii) represent methyl, ethyl, «-propyl, 2-propyl, «-butyl, iso- butyl, sec-butyl, and tert-bvXy ⁇ , respectively
• diethyl (C 1 -C 4 alkyl) malonates examples include diethyl methyl malonate, diethyl ethyl malonate, diethyl isopropyl malonate, diethyl «-propyl malonate, diethyl n- butyl malonate (all from Sigma- Aldrich, Acros Organics, or Alfa Aesar), diethyl isobutyl malonate, and diethyl sec-butyl malonate (both from Alfa Aesar).
• diethyl malonate may be combined with a base such as potassium carbonate and an appropriate alkylating agent such as methyl iodide, ethyl iodide, «-propyl bromide, or «-butyl bromide under microwave irradiation in the method described by Keglevich et al. in Letters in Organic Chemistry, 2008, 5(3), 224-228 and in Green Chemistry, 2006, 5(12), 1073-1075.
• base such as potassium carbonate
• an appropriate alkylating agent such as methyl iodide, ethyl iodide, «-propyl bromide, or «-butyl bromide under microwave irradiation in the method described by Keglevich et al. in Letters in Organic Chemistry, 2008, 5(3), 224-228 and in Green Chemistry, 2006, 5(12), 1073-1075.
• diethyl (C C 4 alkyl) malonates include the reaction of diethyl malonate with an appropriate alkylating agent such as ethyl iodide, isopropyl bromide, isobutyl bromide, or sec-butyl bromide in the presence of a base such as sodium ethoxide in an organic solvent such as ethanol as described in Patel and Ryono in Bioorganic and Medicinal Chemistry Letters, 1992, 2(9), 1089-1092 and elsewhere.
• an appropriate alkylating agent such as ethyl iodide, isopropyl bromide, isobutyl bromide, or sec-butyl bromide
• a base such as sodium ethoxide
• organic solvent such as ethanol
• Carboxylic ester intermediates 14 possessing a gem-dimethyl substitution at the carbon atom a to the ester carbonyl group may be prepared by the methylation of the corresponding mo «o-a-methyl ester intermediate (stereochemical mixture) 14(a-o)b/c(i) as shown in Scheme 7b and reported in Shibasaki, M. et al, in Chemical and Pharmaceutical Bulletin, 1989, 37(6), 1647-1649.
• Scheme 7c illustrates mo «o-alkylations of commercially available or prepared carboxylic esters 14(a-o)a with an alkylating agent R'VR ⁇ X 1 , wherein the R 4 /R 5 group is a C C 4 alkyl group and X 1 is a leaving group such as iodide or bromide to provide the corresponding mo «o-alkylated analogsl4(a-o)b/c, respectively.
• mo «o-alkylated carboxylic ester analogs may be alkylated a second time; for example, mo «o-methylated carboxylic acid esters (stereochemical mixture) 14(a-o)b/c(i) may be methylated a second time to provide the corresponding gem-dimethyl substituted esters 14(a-o)d(i), as illustrated in Scheme 7d.
• Scheme 7e illustrates the preparation of 1 -R 6 -substituted C 3 -C 5
• Stereopure carboxylic esters 14(a-o)b(i-viii) and their stereoisomers, 14(a- o)c(i-viii) may be prepared according to the route illustrated in Scheme 7f.
• Alkylation of an appropriately-substituted carboxylic acid starting material, such as propionic acid (R 4 /R 5 is a methyl group) at the carbon position alpha to the acid carbonyl group by treatment of the acid with an appropriate base, such as lithium diisopropylamide (about two molar equivalents) in the presence of a suitable solvent, such as THF, with an alkylating agent R 6 -X x (Step A) provides the corresponding carboxylic acid intermediates 20(a-o)b/c(i-viii).
• Step B Subsequent coupling of the carboxylic acid intermediate with N- hydroxysuccinimide (NHS) forms the corresponding NHS ester (an activated ester) stereoisomeric mixture 18(a-o)b/c(i-viii) (Step B).
• Step B Treatment of the activated ester stereoisomeric mixture 18(a-o)b/c(i-viii) with (i?)-2-amino-2-phenylethanol in THF results in the mixture of two amide diastereomers 19(a-o)b(i-viii) and 19(a-o)c(i-viii) (Step C), which may be separated by chromatography to provide each pure diastereomer (Step D).
• Recrystallization of the individual diastereomers may provide amides with even greater de purity.
• Amide hydrolysis of each diastereomer to its corresponding carboxylic acid 20(a-o)b(i-viii) and 20(a-o)c(i-viii), respectively (Step E), and subsequent esterification (Step F) provides corresponding individual carboxylic ester stereoisomers 14(a-o)b(i-viii) and 14(a-o)c(i-viii), respectively.
• Scheme 7g shows a synthetic pathway to stereopure carboxylic esters 14(a- o)b(i-vii) (R 5 is hydrogen) employing the use of the chiral auxiliary to generate "(5)-3- (B-carbonyl)-4-benzyloxazolidin-2-ones" 21(a-o)a (both R 4 and R 5 are hydrogen) for more-efficient (asymmetric) alkylation in Step C to provide the corresponding alkylated.
• "(5)-3-(B-carbonyl)-4-benzyloxazolidin-2-ones” analogs enriched in the 21(a-o)b(i-vii) stereoisomer over the 21(a-o)c(i-vii) stereoisomer.
• Step D Removal of the chiral auxiliary (Step D) following alkylation and subsequent chiral amide derivatization (Steps E and F) provides the diastereomers 19(a-o)b(i-vii) separable by chromatography and further purified by crystallization (Step G).
• Acid-catalyzed amide hydrolysis (Step H) to the corresponding stereopure carboxylic acid 20(a-o)b(i-vii) and subsequent esterification (Step I) provide the desired stereopure carboxylic ester intermediates 14(a-o)b(i-vii), which can be carried onto their corresponding stereopure ⁇ -keto phosphonate esters 15(a- o)b(i-vii).
• Scheme 8 illustrates the conversions of acetylenic carboxylic esters 14(a-f)a and 14(a-f)(b-e)(i-xi) to the corresponding ⁇ -keto phosphonates by the previously- described general manner (Step A) and subsequent catalytic hydrogenation (Step B) to provide the corresponding saturated analogs.
• Carboxylic Phosphonate Carboxylic NHS (S)-3-(B-Carbonyl)- Esters 14 Esters 15 Acids 20 Esters 18 Amides 19 4-benzyloxazolidin-2-ones 21
• R 5 C C 4 alkyl * ad(ii) Et Et
• Carboxylic Phosphonate Carboxylic NHS (S)-3-(B-Carbonyl)- Esters 14 Esters 15 Acids 20 Esters 18 Amides 19 4-benzyloxazolidin-2-ones 21
• R 4 and/or R 5 C C 4 alkyl* bd(ii) Et Et
• R 4 and R 5 may both be C r C 4 alkyl bd(vii) sec-Bu sec-Bu
• Carboxylic Phosphonate Carboxylic NHS (S)-3-(B-Carbonyl)- Esters 14 Esters 15 Acids 20 Esters 18 Amides 19 4-benzyloxazolidin-2-ones 21
• Carboxylic Phosphonate Carboxylic NHS (S)-3-(B-Carbonyl)- Esters 14 Esters 15 Acids 20 Esters 18 Amides 19 4-benzyloxazolidin-2-ones 21
• Carboxylic Phosphonate Carboxylic NHS (S)-3-(B-Carbonyl)- Esters 14 Esters 15 Acids 20 Esters 18 Amides 19 4-benzyloxazolidin-2-ones 21
• R 4 and/or R 5 C r C 4 alkyl* ed(ii) Et Et
• Carboxylic Phosphonate Carboxylic NHS (S)-3-(B-Carbonyl)- Esters 14 Esters 15 Acids 20 Esters 18 Amides 19 4-benzyloxazolidin-2-ones 21
• Carboxylic Phosphonate Carboxylic NHS (S)-3-(B-Carbonyl)- Esters 14 Esters 15 Acids 20 Esters 18 Amides 19 4-benzyloxazolidin-2-ones 21
• R 4 and/or R 5 C C 4 alkyl* gd(ii) Et Et
• R 4 and R 5 may both be C r C 4 alkyl gd(vii) sec-Bu sec-Bu
• Carboxylic Phosphonate Carboxylic NHS (S)-3-(B-Carbonyl)- Esters 14 Esters 15 Acids 20 Esters 18 Amides 19 4-benzyloxazolidin-2-ones 21
• R 4 and/or R 5 C C 4 alkyl* hd(ii) Et Et
• R 4 and R 5 may both be C r C 4 alkyl hd(vii) sec-Bu sec-Bu
• Carboxylic Phosphonate Carboxylic NHS (S)-3-(B-Carbonyl)- Esters 14 Esters 15 Acids 20 Esters 18 Amides 19 4-benzyloxazolidin-2-ones 21
• R 4 and/or R 5 C C 4 alkyl* id(ii) Et Et

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• 2014
  • 2014-07-18 EP EP14750837.8A patent/EP3021879A2/en not_active Withdrawn
  • 2014-07-18 AU AU2014290512A patent/AU2014290512A1/en not_active Abandoned
  • 2014-07-18 US US14/905,663 patent/US10729810B2/en active Active
  • 2014-07-18 CN CN201480039423.2A patent/CN105392505A/zh active Pending
  • 2014-07-18 CA CA2910398A patent/CA2910398A1/en not_active Abandoned
  • 2014-07-18 KR KR1020167001059A patent/KR20160048054A/ko not_active Application Discontinuation
  • 2014-07-18 JP JP2016527117A patent/JP2016527006A/ja active Pending
  • 2014-07-18 WO PCT/US2014/047138 patent/WO2015009991A2/en active Application Filing
• 2015
  • 2015-12-22 PH PH12015502854A patent/PH12015502854A1/en unknown

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